<4D F736F F F696E74202D20BBFDBEE0C0C7BCBABAD BC8A3C8AF20B8F0B5E55D>

Transcription

1 IV. 생약의성분

2 Why are plants useful as medicines?

3 Plants as Chemists Plants produce > 10,000 different compounds So, why do plants produce all these chemicals? Plants live by their chemical wits. --Richard Schultes

4 Two theories exist The Random Strategy - Chemicals by Accident - o excretory, so metabolic compounds accumulate Evolutionary Strategy - Chemicals for Survival - Protection from herbivory & predation - Chemicals (e.g., compounds) and physical structures (e.g., thorns)

5 1. 생약성분의분류 (1) 화학구조에따른분류 ; terpenoid, steroid, flavonoid (2) 물성에의한분류 ; alkaloid, saponin, tannin, 식물색소, 정유.. (3) 생리활성에의한분류 ; 항생물질, 비타민, 호르몬, 강심배당체.. (4) 기원에의한분류 ; 식물, 동물, 균류의대사산물, 지의류.. (5) 생합성경로에의한분류 ; polyketide, shikimate, mevalonate, amino acid, 혼합경로

6 2. 식물성분생합성 Biosynthesis Combination of building blocks Secondary metabolism Building block Construction mechanism

7 Primary Metabolism and Secondary Metabolism 1. Primary Metabolism (>>> Primary Metabolite) - Metabolic process including photosynthetic processes producing simple and widely distributed low molecular weight carboxylic acids α-amino acids carbohydrates fatty acids proteins - Starting material (precursor) of the secondary metabolites - Similar 2. Secondary metabolism (>>> Secondary Metabolite) - ard to define - Secondary metabolism is closely connected with several external factors Replicatory growth Flowering (flavonoids) Season, temperature abitat Length of daylight Exposure of wound

8 hν A TYPICAL PLAT Primary Metabolism Glycolysis Photosynthesis (daytime) Respiration (nighttime) 2 2 C 2 2 TRACE METALS a, Ca, K, Mg Fe, Cu, Co, Mo 2 bacteria 2 - /3 - /4 +

9 Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's survivability, fecundity, or aesthetics, or perhaps in no significant change at all. Secondary metabolites are often restricted to a narrow set of species within a phylogenetic group. Secondary metabolites often play an important role in plant defense against herbivory and other interspecies defenses. umans use secondary metabolites as medicines, flavorings, and recreational drugs. [Wikipedia] Secondary metabolism (also called special metabolism) is a term for pathways and small molecule products of metabolism that are not absolutely required for the survival of the organism. Examples of the products include antibiotics and pigments. To distinguish non-secondary ("ordinary") metabolism, the term basic metabolism is sometimes used. Secondary metabolites are produced by microbes, plants, fungi and animals, but not by all of them. [Wikipedia]

10 일차대사과정과이차대사과정 Shikimate Pathway Acetate Pathway Mevalonate Pathway Alkaloids

11 Secondary metabolism Primary metabolism Time Profiles of Glucose, Penicillin, Biomass Concentrations and Dissolved xygen.

12 Intermediates linking primary and secondary metabolism

13 Secondary Metabolism? Combination of building blocks Can be used like a molecular Lego piece.. well, sort of..

14 Building Blocks?

15 Building Blocks? C1: The simplest of the building blocks is composed of a single carbon atom, usually in the form of a methyl group, and most frequently it is attached to oxygen or nitrogen, but occasionally to carbon. C2: A two-carbon unit may be supplied by acetyl-coa. This could be a simple acetyl group, as in an ester, but more frequently it forms part of a long alkyl chain (as in a fatty acid) or may be part of an aromatic system (e.g. phenols). C5: The branched-chain C5 isoprene unit is a feature of compounds formed from mevalonate. Mevalonate itself is the product from three acetyl-coa molecules, but only five of mevalonate s six carbons are used, the carboxyl group being lost. C6C3: This refers to a phenylpropyl unit and is obtained from the carbon skeleton of either L-phenylalanine or L- tyrosine, two of the shikimate-derived aromatic amino acids. This, of course, requires loss of the amino group. Sometimes the side chain is cleaved, removing one or two carbons. Thus, C6C2 and C6C1 units represent modified shortened forms of the C6C3 system.

16 Building Blocks? C6C2: Again, this building block is formed from either L-phenylalanine or L-tyrosine. In the elaboration of this unit, the carboxyl carbon of the amino acid is removed. indole.c2: The third of the aromatic amino acids is L-tryptophan. This indole-containing system can undergo decarboxylation in a similar way to L-phenylalanine and L-tyrosine so providing the remainder of the skeleton as an indole.c2 unit. C4: The C4 unit is usually found as a heterocyclic pyrrolidine system and is produced from the non-protein amino acid L-ornithine. In marked contrast to the C6C2 and indole.c2 units described above, ornithine supplies not its α-amino nitrogen, but the δ-amino nitrogen. The carboxylic acid function and the α-amino nitrogen are both lost. C5: This is produced in exactly the same way as the C4 unit, but using L-lysine as precursor. The ε-amino nitrogen is retained, and the unit tends to be found as a piperidine ring system.

17 Building Blocks?

18 Construction Mechanism Most reactions in secondary metabolic pathways are catalyzed by specific enzymes. Secondary metabolic enzymes may be divided in two groups according to substrate specificity; (1) The enzymes forming the basic skeletons of secondary products, which usually have a high substrate specificity (2) Those modifying the basic skeletons, e.g. certain dehydrogenases, monooxygenases, methyltransferases & glycosyltransferases, which possess a relatively low substrate specificity. metabolic grids A 3 G I B 2 C 3 E D 3 F 5 K

19 Construction Mechanisms Alkylation Reactions; ucleophilic Substitution Alkylation Reactions; Electrophilic Additions Wagner-Meerwein Rearragement Aldol & Claisen Reaction Schiff Base formation & Mannich Reaction Transamination Decarboxylation Reaction xidation & Reduction Reaction; Dehydrogenase, oxidase, Monooxygenase, Dioxygenase, Amine xidase Phenolic xidative Coupling Reactions Glycosylation Reactions

20

21

22

23 Examples 2 C C 3 C C 3 C 3 orsellinic acid 4 x C 2 podophyllotoxin 2 x C 6 C x C 1 parthenolide 3 x C 5 3 C Rha Glc- C 3 C 3 C 3 C naringin C 6 C x C 2 + Sugars tetrahydrocannabinolic acid 6 x C x C 5 papaverine C 6 C 2 + (C 6 C 2 ) + 4 x C 1 C C 3 CC 3 C 3 lysergic acid indole.c 2 + C 5 + C 1 cocaine C x C 2 + (C 6 C 1 ) + 2 x C 1

24 Secondary Metabolites 1. Characteristics of Secondary Metabolites - Taxonomically restricted distribution - ne gene, one enzyme, one product theory - Biosynthesis is controlled by amount & activity of enzyme - Compartmentalization of enzyme, precursors, intermediates & products - Very diverse & complex structures - eeds for cell itself are unclear and rare

25 2. Significance of Secondary Metabolism for the Producer rganism - Process of detoxification - Physiologically active - Chemical signals (interorganismic signals) - Intraspecific signal - Mediating ecologic relationships

26 [ Intraspecific signals ] - Microorganisms sirenin - Plants fucoserraten ectocarpen multifiden: gamate attractrant of brown alga Cutleria multifida fucoserraten ectocarpene multifiden - Insects bombykol cis-verbenol pyrrole compound queen substance (9-oxo-2-decenoic acid) bombykol 3 C CC 3 pyrrole 9-oxo-2-decenoic acid cis-verbenol C

27 - Mammals muscone propionic acid butyric acid androsterone deriv. crotylmercaptane isopentylmercaptane C 3 muscone androsterone deriv.

28 [ Mediating Ecologic Relationship ] - For defense tetrodotoxin batrochotoxin samandarin bufotoxins formic acid - Antibiotics, microbial defense products - Plant-Plant interations 1,8-cineole from Salvia leucophylla juglone from Juglans regia - Plant-Microorganism interactions - preinfectious barriers - preinfectious toxins - prototoxins - phytoalexins-high phenolic compounds

29 - Plant-Animal interactions - attraction of pollinators: nectars, colors, scent - seed dispersal: color, smell, taste - attracting of repelling predator: cardenolides, sinigrin, warbuganal S-Glc 2 C C C 2 C S 3 K sinigrin cardenolide (digitoxigenin) warbuganal C C - Colored secondary products as signals - bright color of mushrooms - fluorescent light

30 3. Polyketide pathway (Acetate-malonate pathway) C 2 hv 2 photosynthesis mono-, oligo-, polyosides erythrose-4 phosphate glucose 1. 수지배당체 GLYCSIDES 2. Polyacetylenes shikimate flavonoids anthocyanins tannins phospho-enol pyruvate phenols, quinones, polyacetylenes macrolides, fatty acids lipids PLYACETATES 3. Phthalides 4. Phloroglucinols pyruvate 5. Quinones SIKIMATES acetyl CoA mevalonate 6. Cannabinoids cinnamates, lignans, coumarins quinones cycle amino acid TERPEES AD STERLS 7. Isocoumarins 8. Chromones proteins ALKALIDS essential oils, sesqui- and diterpenes, saponins, cardenolides carotenes

31 ACETYL CEZYME A - A TW-CARB BUILDIG BLCK Acetyl CoA C 3 C S CoA C-C C-C C-C C C Can be used like a molecular Lego piece.. well, sort of.. C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C C C-C C-C C-C C-C C-C C-C C-C C-C C C C-C

32 CLAISE CDESATI R C 2 C C 2 C 3 + ac 2 C 3 a β-ketoester R C 2 C C C C 2 C 3 R + R C 2 C C 2 C 3 C 3 C 2 Acidic α-hydrogens are removed in strong base to make an enolate anion which adds to the C= of another molecule. - C : : : C R C C R

33 CLAISE CDESATI Vs. ALDL CDESATI Claisen condensation Base-catalyzed condensations between ester and compound posessing active methylene groups R C C R' 2 C C C 2 5 R C C C C 2 5 R' Aldol condensation Condensation of two carbonyl compounds (e.g., aldehyde and ketone) to form an aldol (β-hydroxy carbonyl compounds) R 2 R 1 C C R 3 a ketone + C R 4 an aldehyde R 2 R 1 C C R 3 C R 4

34

35 2 분자의탄소를갖는 acetate 단위구조 C 3 C S CoA C 3 C acetic acid acetate unit acetyl CoA

36 ACETYL CoA UITS ARE LIKED BY A CLAISE-LIKE LIKE CDESATI Strong bases are not tolerated by biological systems. ature does these condensations using malonyl CoA. C 2 C S CoA :B ATP ADP C C 2 Biotin C S CoA Biotin Biotin-C C C C 2 S malonyl CoA CoA Malonyl CoA 생합성

37 WY TIESTERS? Differences between an oxygen ester and a thioester: Thioesters are more prone to enolization. Thioesters are more reactive.

38 TE EZYMES TAT ASSEMBLE ACETYL-CoA CoA UITS USE A DECARBXYLATI F MALYL-CoA CAI EXTEDER malonyl CoA Enz-B: x1 C acetyl CoA STARTER C 3 C C 2 C C 2 C.. a polyketide chain C 2 C S CoA C 3 C S CoA C 2 C C 2 C SCoA Enz-B: x2 - C 2 x5 x4 C.. C C 2 S CoA C C C 2 S CoA C 3 C C 2 C2 C S CoA C 3 x3

39 Acetate-malonate pathway (= Polyketide pathway) : acetyl CoA 또는 acyl CoA 를출발물질로하여 malonyl CoA 가반응하여생성 3 C C SCoA 3 C C SCoA 3 C C SCoA acetyl-coa Claisen reaction 3 C C C 2 C SCoA acetoacetyl-coa Claisen reaction 3 C C C 2 C C 2 C n SCoA poly-β-keto ester 3 C C SCoA acetyl-coa 2 C C SCoA Claisen reaction 3 C C C 2 SCoA C SCoA 3 C C C 2 C acetoacetyl-coa SCoA malonyl-coa C 2 nucleophilic attack on carbonyl with simultaneous loss of C 2 malonyl-coa C 2 3 C C C 2 C C 2 C n poly-β-keto ester SCoA

40 2-UIT 의 polyketide 는가능한 2 개의 reactive carbonyl carbon 을가진다. C.. C 2 C S CoA C 3 C S CoA C C 3 C 2 - C 2 2 C 1 S CoA BRACED LIEAR mevalonic acid C 3 C C 3 C C 2 C S CoA C 3 C C C C C2 2 SCoA C 2 C 2 C 2 C 2 C 2 C C SCoA PLYKETIDE CAIS TERPEES STERIDS ACETGEIS

41 cys -S TE ASSEMBLY EZYMES acetyl - malonyl transferases acetylcoa starter C C 3 S CoA +.. cys -S C C 3 CoAS C C.. 2 C C 2 -S -S malonylcoa.. extender C 2 -S.. -S.. -S etc. more malonylcoa s -S -S C 2 :B :B :B - C 2 - C 2 - C 2 acyl carrier protein (ACP) C 3 C C 2 C C 2 C C 2 C SCoA

42 BUILDIG TE CAI A FLEXIBLE LIK + ATER MDEL F TE EZYME -S S C C3 - C 2 -S- -S -S C C2 C -S C C 2 C 3 transfer + S C C2 C 3 -S C C2 C 3 -S C C2 C Malonyl-CoA -S - C 2 -S Growing chain C -S C C C2 2 C 3 etc

43 지방산생합성과정에서 ACP 의역할

44

45 Polyketides: large class of natural products derived poly-β-keto chains 종류 fatty acid polyacetylenes prostaglandins macrolide antibiotics 3 C C C 2 C C 2 n C SCoA poly-β-keto ester many aromatic compounds- anthraquinones, tetracyclines

46 Polyketides are the precursors C 3 C C 2 C C 2 C C 2 C SCoA of the class of natural products called acetogenins C 3 C 2 2 hydrolysis - CoAS SCoA C 3 C 2 internal aldol condensation C 3 enolization rsellinic acid ( Lichen spp ) C 3 an acetogenin made from acetate units - 2 dehydration makes aromatic ring C 3

47 SME TER SIMPLE ACETGEIS internal Claisen 1) enolization 2) SAM Me SEnz Me Me Eugenone ( oil of cloves ) C 3 SEnz (found in Lichen )

48 Polyketide 계생약성분의 cyclization 방법 d c C 3 CC 2 CC 2 CC 2 CCoA b a b d c C a xanthoxylin orsellinic acid C

49 1. 수지배당체 (Resin glycosides) pharbitin: 견우자 (Pharbitis nil) 의씨앗 - 사하성분 pharbitin 3 C (C 2 ) 2 C (C 2 ) 7 C 2 C C 2 2 Glc Glc Rha 6 Rha 4 Qui R 3 pharbitic acid C, R= pharbitic acid D, R=Rha (+)-α-methylbutyric acid + nilic acid tiglic acid valeric acid

50 2. Polyacetylene 계화합물 분포 : 고등식물- Compositae, Umbelliferae 하등식물- 담자균류 (Basidomycetes) 활성 : G(+), G(-) bacteria, unstable 분포생약 인진호 - capillarin, capillin ( 백선균생육저지, 담즙분비촉진 ) 일당귀 - falcarindiol, falcarinol (=panaxynol), falcarinolone- 진통작용 C 2 C C C 3 C C C C C 3 capillin capillarin 2 C C C C C C C C C R C (C 2 ) 6 C 3 2 C C C C C C C C C C (C 2 ) 6 C 3 falcarindiol, R= falcarinol, R= (panaxynol) falcarinolone

51

52 3. Phthalide 계화합물 α-pyrone ring과유사한 lactone ring을가진화합물 분포생약 - 천궁 (Cnidium officinale): cnidilide, liguistilide - 일당귀 (Angelica acutiloba): butyldienephthalide, ligustilide - 아편 (Papavera somniferum): meconin - 자실 (Catalpa ovata): catalpalactone 3 C C 3 cnidilide ligustilide butyldenephthalide 3 C C 3 meconin 3 C C 3 catalpalactone

53 참당귀 : Angelica gigas akai 주요성분 : Coumarin: decursin, decursinol angelate decursinol 일당귀 : Angelica autiloba Kitagawa 주요성분 : Phthalide: ligustilide, butylidenephthalide, butylphthalide Polyacetylene: falcarindiol, falcarinol, falcarinolne 3 C C 3 decursin decursinol ligustilide butyldenephthalide falcarinol

54 Aromatic polyketide SCoA + 3 x acetyl-coa C SCoA malonyl-coa poly-β-keto ester SEnz folding A folding B aldol addition on to carbonyl SEnz SEnz aldol reaction Claisen reaction dehydration favored by formation of conjugated system SEnz SEnz re-formation of carbonyl possible by expulsion of leaving group SEnz enolization hydrolysis enolization favored by formation of aromatic ring orsellinic acid phloracetophenone enolization enolization favored by formation of aromatic ring Resorcinol derivatives - R has odd number of C Phloroglucinol derivatives - R has even number of C

55 4. Phloroglucinols Phloroglucinol ring을가지는화합물 represented as a tautomeric triketone - 관중 (Drypteris crassirhizoma): aspidin, albaspidin, aspidinol- 조충구제 - 인도대마초 : cannabinolides-향정신성약물 - 홉프 (umulus lupulus): humulone, lupulone-맥주의고미성분-고미, 진정, 항균 - 저목 (Mallotus phillippinensis): rottlerin-조충구제 - 코소화 : α-kosin, β-kosin aspidin albaspidin humulone lupulone

56 5. Quinones Quinonoid 란 quinone 성이있는화합물을비롯하여쉽게 quinone 성화합물로변 형될수있거나또는생합성적으로이들과밀접한관련이있는화합물의총칭 1) benzoquinones 2) naphtoquinone 3) anthraquinone 4) phenanthraquinone benzoquinone naphthoquinone anthraquinone phenanthraquinone

57 5-1. Benzoquinones ubiquinone: Coenzyme Q, mitochondria 내에서전자전달 coenzyme plastoquinone: 엽록체존재, 광합성에서의전자전달에관여 mitomycin: Streptomyces caespitosus 가생산하는항균, 항종양성항생물질 - DA 합성, 유사분열저해 embelin: Embercia ribes 과실의등색색소 rapanone: Rapanea maximowiczii maesaquinone: Maesa joponica n ubiquinones, n=1~12 3 C 2 3 C plastoquinone 9 3 C mitomycin 2 3 C C 3 R 3 C maesaquinone embelin, R=C rapanone, R=C 13 27

58 polyporic acid: Ployporus nidulans 의목재부패균의청동색색소 asteriquinone: Aspergillus terreus perezone: Compositae, Perezia adnata 에함유된등색색소 3 C polyporic acid perezone asterriquinone

59 5-2. aphtoquinones 다양한생합성경로를통하여생성 1) acetate-malonate pathway (=polyketide pathway) 2) shikimate-mevalonate pathway 3) mevalonate pathway 2) 1) C 3 C SEnz javanicin C C R 2 R 1 shikimic acid p-hydroxybenzoic acid shikonin, R 1 =, R 2 = alkannin, R 1 =, R 2 = 3) coleone A

60 4) Shikimate pathway (iso-chorismic pathway) + MVA C oxoglutaric acid C C C C thiamin pyrophosphate C C shikimic acid iso-chorismic acid o-succinylbenzoic acid C Vitamin K or C lawsone juglone lapachol dannione

61 - vitamine K: phylloquinone (Vit. K1) menaquinone (Vit. K2) 생체내전자전달계에관여, 혈액응고인자 (prothrombin) 의수준유지 - lawsone: Impatiens balsamina, Lawsonia alba의황색색소 - lapachol, isolapachol: Bignoniaceae ( 능소화과 ) 의심재에존재 - shikonin, acetylshikonin: Lithosperma erythrorhizon의적등색색소, - alkannin: Alkanna tinctoria의뿌리의적색소 - dunninone: Streptocarpus dunnii잎의선모에서분비되는둥적색의색소 - juglone: 호두 3 n C 3 C 3 phyllaquinone menaquinones, n=6~9 dunnione R 2 R 1 lawsone lapachol shikonin, R 1 =, R 2 = alkannin, R 1 =, R 2 = juglone

62 5-3. Anthraquinones Acetate-malonate pathway (emodin type): 산소원자가방향환상에하나씩건너서 Polygonaceae ( 대황, 호장근, 하수오 ), Leguminosae ( 센나엽, 결명자, 크리사로빈 ) Rhamnaceae ( 카스카라사그라다껍질, 후랑굴라껍질 ), Liliaceae ( 노회 = 알로에 ) Shikimate pathway (alizarin type): 산소원자가방향환의한쪽에치우침 Rubiaceae, Bignoniaceae, Verbenaceae, Acetate-malonate (polyketide pathway): emodin type Shikimate/2-oxyglutarate/mevalonate: alizarin type C 3 emodin aloe-emodin alizarin lucidin

63 Anthraquinones aldol reactions - 2 ADP SEnz ADP ADP reduces carbonyl emodin: 사하성분 Polygonaceae; Rheum palmatum Leguminosae; Cassia Rhamnaceae - often glycosides aloe-emodin: Aloe vera physicon rhein C C C C hypothetical intermideate 1 hypothetical intermideate 2 hypothetical intermideate2 decarboxylation faciliatated by ortho-hydroxyl endocrocin enolizations oxidation -C 2-2 enolization oxidation -C 2 crysophanol oxidation of methyl to alcohol islandicin - 2 enolization 2x oxidation -C 2 C emodin aloe-emodin oxidation of alcohol to acid rhein -methylation of phenol SAM 3 C physicon

64

65 ATRAQUIE LAXATIVES SEnz Me physicon emodin Glu Glu aloe-emodin rhein cascaroside

66 GRISEFULVI Me SAM SEnz Aldol Me Cl+.. Claisen Me. reson. Me [] Me Me Cl. Me Cl.. Me Cl Me Me Me SAM FAD 2 Me Me Me Me Me Cl Cl Cl griseofulvin

67 MACRLIDES (LARGE RIGS) 9 units SEnz ADP aromatize aldol SEnz lactonize.. ADP, then dehydrate acetylcoa + 8 malonylcoa ADP, then dehydrate, then FAD 2 macrolide antibiotic The various reductions may be performed during the chain extension steps rather than afterward. zearalenone Gibberalla zeae

68 Anthraquinones C alizarin: Rubiaceae; Rubia tinctorium C shikimic acid phosphoenolpyruvate C iso-chorismic acid C thiamin pyrophosphate C C C oxoglutaric acid C C o-succinylbenzoic acid C C R Shikimate pathway (alizarin type): - 산소원자가방향환의한쪽에치우침 - shikimate/2-oxoglutarate/mevalonate alizarin lucidin C 3 tectoquinone, R= 3-hydroxy-2-methylanthraquinone, R= C 3 morindone

69 Anthraquinones 대장의연동운동을촉진하여사하작용을나타냄 활성형 : anthrone 활성강도 : dianthrone 유도체 > anthrone 배당체 > 유리형 anthraquinone 배당체는결합당의개수가증가할수록약효증가 : 수용성증가, 위장관흡수량감소 배당체는수용성을높여비당체를대장까지운반하고, 운반된 anthraquinone 배당체는가수분해, 환원환 원적분해에의하여 anthrone 으로되어활성을나타냄 채취후 1 년경과품사용 신선품에많이함유된 anthranol 은구토, 출혈을일으키는등작용이너무강함 산화되어 anthraquinone 으로되면작용이완화되어부작용감소 확인반응 :Bornträger 반응 -anthraquinone 에 alkali 를가하면 a-anthraquinone 으로되면서적색으로정색 Glc Glc 6 R 2 C R 1 sennoside A, R 1 =C, R 2 =, threo sennoside B, R 1 =C,R 2 =, erythro sennoside C, R 1 =C 2, R 2 =, threo sennoside D, R 1 =C 2, R 2 =, erythro sennoside E, R 1 =C, R 2 =C-C, threo sennoside F,R 1 =C, R 2 =C-C, erythro [ ] [ ] [ ] [ ] anthranol anthrone anthraquinone R 2 R 1 chrysophanol, R 1 =C 3,R 2 = emodin, R 1 =C 3, R 2 = aloe-emodin,r 1 =C 2, R 2 = rhein, R 1 =C, R 2 = physcion, R 1 =C 3, R 2 =C 3

70 5-4. Phenanthraquinones tanshinone I, IIA,dihydrotanshinone I, methylenetanshiquinone, cryptotanshinone, danshenxinkun B: 단삼 (Salvia miltiorihza Bunge), 월경부조, 협심증, 불면증, 요통 C 3 C 3 C 3 C 3 tanshinone I cryptotanshinone methylenetanshiquinone C 3 C 3 C 3 dihydrotanshinone I tanshinone IIA C 3 danshenxinkun B

71 5-5. Extended Quinones Poly-ring quinone: ypericaceae, Polygonaceae, Bacteria - hypericin: ypericum- St.John s worth, photodynamic effect, 항우울제, 방부제 - elsinochrome A: Elicinoe- photodynamic effect 3 C 3 C R C 3 3 C C 3 3 C C 3 C 3 hypericin, R= pseudohypericin, R=C 2 elisinochrome A

72 6. Cannabinoid - 인도대마의환각작용성분 - hexaketide 와 2 개의 isoprene 이결합 C tetrahydrocannabinolic acid 6 x C x C 5 8. Chromone류 benzopyran-4-one을기본골격으로하는화합물 - C 2 에 methyl group 또는 hydroxymethyl group 가짐 - Umbelliferae, Leguminosae, Myrtaceae, Sapindaceae - 암미실 : Ammi visnaga- visnagin, khellin-혈관확장작용 - 인진호 : Artemisia capillaries- capillarisin-이담작용 - 정향 : Eugenia caryophyllata- eugenin - 승마 : Cimicifuga heracleifolia- cimifugin- 중추억제 7. isocoumarin benzopyran-1-one을기본골격으로하는화합물 - coumarin에비해수도적고분포도한정 - 감다 : ydrangea macrophylla-phyllodulcin- 감미료 - 인진호 :Artemisia capillaries-capillarin 이담작용 3 C eugenin C 3 3 C C 3 3 C C 3 cimifugin C 2 visnagin C 3 capillarin (+)-phyllodulcin C 3 C 3 khellin C 3 3 C capillarisin

73 1-2-benzopyran-1-one isocoumarin 4-1-benzopyran-4-one chromone 2-1-benzopyran-2-one coumarin

74 Isocoumarin 의생합성 C 3 SCoA 3 C SCoA C

75 Chromone 의생합성 Claisen reaction, aromatization eterocyclic ring formation via Michael-type nucleophilic attack of on to enol tautomer followed by loss of leaving group SEnz oxidative cleavage of side-chain cyclization of hydroxyl on to dimethylallyl group C-alkylation SAM 3 C visnagin visamminol hydroxylation SAM 1' 2' 3' 5 3 C peucenin C khellin PP DMAPP ,7-dihydroxy-2- methylchromone

76 Different starters and extenders Fatty acyl-coa ester Starter SCoA 3 X malonyl-coa reduction palmitoleyl-coa EnzS Fatty acyl-coa ester aldol reaction -C 2 hydroxylation urushiol anacardic acid C

77 exanoyl-coa Starter CoAS hexanoyl-coa 3 X malonyl-coa SEnz aldol C pentylresorcylic acid oxidation to allylic cation; allows change in configuration around double bone E geranyl PP PP - C 2 electrophilic cyclization onto carbocation, followed by loss of proton cannabigerol C-alkylation olivetol protonation of double bond to give carbocation allows nucleophilic attack of hydroxyl sequential oxidation of cyclohexane gives aromatic rings cannabidiol CBD tetrahydrocannabinol TC cannabinol CB

78 Propionyl-CoA Starter CoAS propionyl-coa 9 X malonyl-coa - anthracyclines - doxorubicin ( 유방암, 자궁내막암, 난소암, 고환암, 폐암등 ) - daunorubicin ( 급성백혈병 ) - FDA 승인 i) glycosylation of 7-hydroxyl ii) hydrolysis of ester iii) decarboxylation of 10-acid iv) oxidation to 13-ketone v) methylation of 4-hydroxyl CC 3 ε-rhodomycinone SEnz TDP-L-daunosamine i) reduction of C= ii) 11-hydroxylation 2 ADP AD(P) TDP-D-glucose aklanonic acid SAM aldol C CC 3 aklaviketone C hydroxylation at C-14 3 C 2 daunorubicin 2 doxorubicin (adriamycin)

79 Malonamyl CoA STARTER 2 C C 2.. cys -S.. -S.. -S.. -S.. -S C S malonamylcoa starter CoA CoAS etc. C C 2 C more malonylcoa s malonylcoa extender + cys -S -S -S -S C C C2 2 C 2 C 2 C 2 :B :B :B - C 2 - C 2 - C 2 acyl carrier protein (ACP) 2 C C 2 C C 2 C C 2 C C 2 C SCoA

80 TETRACYCLIES SEnz Cl Me 2 actually starts from malonamyl CoA which can also form polyketides 2 chlortetracycline 2 2 C C 2 C S malonamyl CoA CoA Me 2 C 3 Cl aureomycin

81 - tetracycline 계항생물질 - 칼슘과쉽게결합 : 신생골과어린이치아에침착 - 소아금기 - 위장관계 : 오심, 구토, 설사 - 장관에직접자극 CoAS 2 8 x malonyl-coa SEnz 2 malonamyl-coa R 4 D R 3 R 2 C R 1 B Me 2 A R 5 tetracycline, R 1 =, R 2 =C 3, R 3 =, R 4 =, R 5 = chlortetracycline, R 1 =, R 2 =C 3, R 3 =, R 4 =Cl, R 5 = oxytetracycline, R 1 =, R 2 =C 3, R 3 =, R 4 =, R 5 = demeclocycline, R 1 =, R 2 =, R 3 =, R 4 =, R 5 = methacycline, R 1 =, R 2 +R 3 ==C 2, R 4 =, R 5 = doxycycline, R 1 =, R 2 =C 3, R 3 =, R 4 =, R 5 = minocycline, R 1 =, R 2 =, R 3 =, R 4 =Me 2, R 5 =

82 Propionyl CoA STARTER & MethylmalonylCoA Extender EXTEDER methylmalonylcoa 6x SCoA C SCoA propionylcoa STARTER CoA S BUILT FRM 3-CARB UITS reduced reduced Enz unchanged S reduced dehydrated reduced reduced reduced lactonization oxidized oxidized D-desoamine Me 2 oxidations Me erythromycin A L-cladinose add sugars

83 - macrolide 계항생물질 - erythromycin: 위산에용해, 장용내피정사용 C SCoA + 6 X SCoA Pripionyl CoA methylmalnonyl CoA SEnz Me 2 Me clarithromycin R 1 R 2 Me 2 Me Me Me 2 erythromycin A, R 1 =, R 2 =Me erythromycin B, R 1 =, R 2 =Me erythromycin C, R 1 =, R 2 = azithromycin

84 Metabolite formation depending on several factors 1. the starter or chain initiating unit 2. the number of acetyl-coa units involved or occasionally other esters such as propinoyl-coa or butyryl-coa 3. the mode of cyclization 4. the condensation of separately synthesized polyketides 5. the secondary processes, such as halogenation, alkylation, redox reactions, rearrangements, etc.

85 4. Shikimate Pathway C 2 hv 2 photosynthesis mono-, oligo-, polyosides erythrose-4 phosphate glucose shikimate flavonoids anthocyanins tannins phospho-enol pyruvate GLYCSIDES phenols, quinones, polyacetylenes macrolides, fatty acids lipids PLYACETATES 1) Phenylpropanoids 2) Coumarins 3) Lignans pyruvate SIKIMATES acetyl CoA mevalonate cinnamates, lignans, coumarins quinones proteins cycle amino acid ALKALIDS TERPEES AD STERLS essential oils, sesqui- and diterpenes, saponins, cardenolides carotenes

86 TE SIKIMIC ACID PATWAY This pathway (unique to plants) leads to the formation of the aromatic amino acids phenylalanine and tyrosine and to the formation of many other phenyl-c3 compounds. C C C Phenylpropanoids Phenyl-C3 Ex) lignan, coumarin, lignin Cleavage of the C3 side chain leads to many phenyl-c1 & phenyl-c2 compounds. C C C C Phenyl-C1 Ex)benzoic acid..

87 The buliding block C6C3: L-phenylalanine, L-tyrosine C 2 L-Phe C C 6 C 2 2 C 6 C 3 L-Tyr C 6 C 1 2 C C 6 C 3 3 C C 3 C 3 podophyllotoxin 2 x C 6 C x C 1

88 pentose phosphate pathway GLUCSE glycolysis RIGIS F TE SIKIMIC ACID PATWAY Erythrose-4-phosphate PEP Phosphoenol pyruvate Shikimic Acid Acetyl-CoA The pentose phosphate pathway is one that converts glucose into sugars of different sizes (different numbers of C) by acyl interchanges. Erythrose is a 4-carbon sugar.

89 FRMATI F SIKIMIC ACID P C 2 phosphoenol pyruvate P C C C 2 + Aldol-type Reaction P B: C 2 -P AD + C C C 2 erythrose-4-phosphate C ADP C C Aldol-type Reaction C 2 + C C C 2 shikimic acid

90 FRMATI F CRISMIC ACID C C hydrolysis of PEP ATP shikimic acid P C 3 C C + pyruvic acid EPSP synthase Inhibitor; glyphosate nucleophilic addition to C= C - 3 P 4 C :B - 2 C C 2 C 2 C 3 C P C P C C C C chorismic acid EPSP (3-enolpyruvylshikimic acid 3-phosphate)

91 PREPEIC ACID chorismic acid C C C 2 C Claisen Type Rearrangement Chorismate mutase C C C 2 C pseudoaxial conformation prephenic acid Prephenic acid can be converted to phenylpyruvic acid or to 4-hydroxyphenylpyruvic acid p-hydroxyphenylpyruvic acid tyrosine ADP -+ - C 2 ADP+ -- an additional oxidation step (of alcohol to ketone) means is retained on decarboxylation and aromatization; no discrete ketone intermediate is formed C C 2 C -+ C - C 2 - decarboxylation, aromatization and loss of leaving group phenypyruvic acid phenylalanine

92 CLAISE REARRAGEMET A TERMAL REARRAGEMET CR heat CR + CR enolization an allyl ether an allyl phenol The Claisen rearrangement is a powerful carbon-carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl

93 PREPEIC ACID T PEYLALAIE C C C 2 C :B-Enz C 2 C C prephenic acid - C 2-2 phenylpyruvic acid + transamination decarboxylation, aromatization and loss of leaving group C 2 C C 2 phenylalanine

94 PREPEIC ACID T TYRSIE C C C 2 C :B-Enz C 2 C C AD+ prephenic acid - C 2 4-hydroxyphenylpyruvic acid hydride transfer to AD+ transamination an additional oxidation step (of alcohol to ketone) means is retained on decarboxylation and aromatization; no discrete ketone intermediate is formed C 2 C C 2 tyrosine

95 PEYLALAIE AD TYRSIE CME FRM A CMM SURCE AD ARE T CVERTED PREPEIC ACID phenylpyruvic acid 4-hydroxyphenylpyruvic acid C 2 C C 2 X C 2 C C 2 phenylalanine tyrosine Although most plants could convert phenylalanine to tyrosine using hydroxylases, this conversion is a minor pathway. Most plants make enough tyrosine without converting phenylalanine.

96 Shikimate Pathways SIKIMIC ACID CRISMIC ACID PREPEIC ACID PEYL-C3 CMPUDS (+ acetogenin piece) FLAVIDS TYRSIE PEYLALAIE CIAMIC ACIDS PEYL-C1 CMPUDS ALKALIDS ALKALIDS

97 CIAMYL CMPUDS C 2 C C The rings can have various numbers of hydroxyl or methoxyl groups (hydroxylases and SAM). ADP C 2 C C C C C cinnamaldehyde C - 2 C C Enz-S ADP C C C S-Enz cinnamic acid FAD 2 oxidative cleavage C 2 C 2 C C hydrocinnamic acid benzaldehyde

98 SME ATURALLY-CCURIG CIAMYL CMPUDS C C C C C Me Me CIAMIC ACID p-coumaric acid caffeic acid ferulic acid corresponding aldehydes are also found - see next slide C 2 C 2 Me Me C 2 Me Me C Me p-coumaryl alcohol coniferyl alcohol sinapyl alcohol sinapic acid

99 TYPICAL REDUCTI SEQUECES C C SCoA C SCoA ADP ADP C 2 Me Me sinapic acid Me Me Me Me sinapyl aldehyde Me Me sinapyl alcohol C C 2 Me estragole (methylchavicol) Me Me Me anethole

100 CLEAVAGE T PEYL-C1 CMPUDS C SCoA C SCoA 2 C SCoA ADP+ C SCoA C C 2 : S CoA Me ferulic acid 2 Me Me Me reverse Claisen C C 2 C C 2 C SCoA Me reverse aldol Me Me vanillic acid Me vanillin

101 phenylpropanoid and lignan 의생합성 C C 2 PAL L-Phe cinnamic acid C 2 ADP C hydroxylation C sequence of hydroxylation and methylation reactions C C C 2 2 ADP SAM 2 ADP SAM L-Tyr 4-coumaric acid p-coumaric acid 3 C 3 C 3 C C 3 caffeic acid ferulic acid sinapic acid C 2 C 2 C 2 4-hydroxycinnamyl alcohol (p-coumaric alcohol) 3 C coniferyl alcohol 3 C C 3 sinapyl alcohol x 2 Lignans Polymers x n Lignins

102 Shikimate 생합성경로 C 2 PAL phenylalanine 2 C cinnamic acid p-coumaric acid C 3 C ferulic acid C 3 C vanillin C ATP CoA 3 C benzoic acid C 6 -C 1 C SCoA 3 C cinnamaldehyde C 6 -C 3 anethole C 6 -C 3 C 3 C 3 C Glc coniferyl alcohol PP umbelliferone psoralen coumarin 3 C Glc 2 x arctiin C 3 C 3 eugenol 3 C C 3 lignin lignan 3 C 3 C 3 C 2 x C 3 gomisin A C 3 C 3

103 1. Phenylpropanoids - phenylalanine, tyrosine 의탈암모니아반응에의하여생성되는 C 6 -C 3 화합물 - 식물정유의주요성분 - cinnamic aldehyde: Lauraceae, 계피정유의주성분 - 혈압강하, 심박수감소말초혈관확장, 진정, 해열, 중추각성 ( 소량 ), 중추억제 ( 다량 ), 진경, 국소자극, 국소마취및항진균작용 - anethole: 회향, 대회향, 아니스실 - 중추억제, 구풍, 혈관확장 - eugenol, methyleugenol: 정향 - 진정, 국소마취항균작용, vanillin 제조원료 - safrole: 세신 - 누에의성작억제 - asarone: 창포 - myristicin: 육두구 - 환각작용 - methyl cis-ferulate: 녹병균 - 발아저해 - coniferin, syringin: 고등식물, 피자식물에잘알려져있음 - C 6 -C 1 화합물 - C 6 -C 3 화합물이 β-oxidation을받아생성 - benzoic acid, benzyl alcohol, benzyl aldehyde 유도체로유리형또는배당체로존재 - vanillin: 식품, 의약품의풍향제로이용 C C 3 C 2 C 2 C 3 C 2 C 3 C 3 C 3 3 C C 3 3 C cinnamaldehyde anethole eugenol safrole asarone myristicin

104 2. Coumarins 2-1-benzopyran-2-one을기본골격으로하는화합물 Umbelliferae, Rutaceae, Leguminosae, Compositae에널리분포 70% 이상이 7번탄소에 oxygen 치환 자외선 (360 nm) 에서청색, 청자색, 황백색의형광을나타냄 골격에따른분류 1) hydroxy and alkyl coumarins 2) furanocoumarins 3) pyranocoumarins 4) dicoumarols (biscoumarin) E Z C hv C coumarin cinnamic acid C C trans-cis isomerazation C 2-coumaric acid C lcatone formation C 7 8 coumarin 1 2 C 4-coumaric acid 2,4-dihydroxycinnamic acid umbelliferone

105 1) hydroxy coumarins and alkyl coumarins aesculin (esculin) 물푸레나무과 (leaceae) 의 Fraxinus속, ippocastanaceae의 Aesculus속식물수피에서 fraxin과함께얻어짐. 진피와서양칠엽수종자- 모세혈관투과성억제, 부종억제, 요산배설촉진 scoparone- 사철쑥 (Artemisia capillaris) 의꽃이삭- 담즙분비촉진 umbelliprenin- Angelica속식물의과실 osthol- 사상자 (Cnidium monniei) 의과실-항진균작용, 호흡중추흥분작용 angelol A- Angelica ursina의뿌리에서발견 scopoletin, scopolin, umbelliferone, flaxetin, herniarin, cycolisin 등 R 1 R 2 R 3 3 C 3 C aesculin, R 1 =Glc, R 2 =, R 3 = fraxin, R 1 =C 3, R 2 =, R 3 =Glc scoparone, R 1 =C 3, R 2 =C 3, R 3 = umbelliferone, R 1 =, R 2 =, R 3 = umbelliprenin, R 1 =, R 2 =farnesyl, R 3 = scopoletin, R 1 =C 3, R 2 =, R 3 = scopolin, R 1 =C 3, R 2 =Glc, R 3 = osthol angelol A

106 2) furanocoumarins psoralen-무화과나무, 보골지 (Psoralea corylifolia), 백선피 (Dictamus albus) 등 - 광감작작용을이용하여백반병치료 imperatorin, oxypeucedanin- 강활 (Angelica koreana) byakangelicin- 백지 (Angelica dahurica) angelicin, xanthotoxin, bergapten, marmesin DMAPP PP C-alkylation at activated position ortho to phenol umbelliferone 2 ADP demethylsuberosin marmesin C 3 psoralen (linear furanocoumarin) bergapten C 3 xanthotoxin imperatorin 3 C C 3 angelicin (angular furanocoumarin) pimoinellin byakangelicin

107 3) pyranocoumarins decursin, decursinol- 당귀 (Angelica gigas), 치매예방효과 visnadin, samidin, dehydrosamidin- 암미실 (Ammi visnaga), 심장의관상혈관확장 (visnadin) membered furan ring nucleophilic attack on to epoxide membered pyran ring decursinol decursin visnadin

108 4) biscoumarins dicoumarol- 자주개자리 (Medicago sativa), Sweet clover (Melitous officinalis), 목축우의출혈성증상유발, 항혈액응고작용 (Vitamin K 의작용저해 ), 혈전증치료및예방 dicoumarol and warfarin 2 warfarin nicoumalone Cl dicoumarol coumatetralyl coumachlor R=, difenacoum R=Br, brodifenacoum R

109 C DICUMARL AD WARFARI SCoA C.. C SCoA : C - 2 cinnamic acid RDETICIDE (rat poison) Warfarin causes internal bleeding in cows dicoumarol (sweet clover) anti-coagulant

110 5) isocoumarin 1-2-benzopyran-1-one을기본골격으로하는화합물 polyketide pathway를거쳐서생합성 고등식물 - 감다 : ydrangea macrophylla-phyllodulcin- 감미료 - 인진호 :Artemisia capillaries- capillarin 이담작용미생물- mellein, reticulol capillarin (+)-phyllodulcin C 3

111 3. Lignans Phenylpropanoid (C 6 -C 3 ) 2개가 side chain의 (β-β' 위치또는 8-8') oxidative coupling 하여생성된화합물 기본탄소골격으로 C 18 을가짐 약 70개과에서수백종이분리되었음 Gymnosperm에서는주로목부에서분리되나, Angiosperm에서는모든부분에서분리됨 종류 : lignan ( 협의 )- β-β' 위치 (8-8') neolignan- lignan의결합위치가 β-β' 위치 ( 또는 8-8') 가아닌화합물 norlignan- 탄소수가하나적은 C17 화합물 sesquilignan- C 6 C 3 unit가 3개결합 dilignan- C 6 C 3 unit가 4개결합 lignoid: flavolignan- flavonoid+lignan (silybin), coumarolignan, xantholignan lignin: p-hydroxycinnamyl, coniferyl, sinapyl alcohol등이중합하여생성되는 polymer 식물의목화 (lignification) 를일으킨다.

112 Phenolic xidative Coupling - - e resonance-stabilizes free radical phenol X 2 coupling of two radicals keto tautomers dienone dienone enolization enol tautomers ether linkage

113 Lignans Principal types of lignans 6 5 α γ 1 4 β a 2b 2c 3 4a 4b 5 6 1: dibenzylbutane, 2a~c: monofuranoid, 3: butyrolalctone 4a~b: arylnaphthalene,5: dibenzocyclooctane, 6: furanofuranoid Examples of neolignan structures

114 Lignans 6 5 α γ C β 2 3 C 3 C 2 C 3 C 2 C 3 C 2 C 3 C 2 C 3 coniferyl alcohol coniferyl alcohol: oxidation and rarical mesomerism C 3 3 C C 2 C 2 C 3 reduction β C 2 C C 3 C 2 C β C C C 3 C 2 C 2 전형적 lignan 의생합성경로 C 3

115 Lignans schisandrin, deoxyshisandrin, gomisin A, D, E, pregomisin: 오미자의 Et 추출물, 간세포보호활성 - GPT 값상승저해, lipid peroxidation 저해, antioxidant effect, SD 활성증가작용, 합성유도체인 BDD (biphenyldimethyldicarboxylate) pinoresinol: 연교 - 소염, 해독 sesamin: 참깨에존재하는 lignan 으로산화방지효과. enterodiol, enterolactone: 사람, 포유동물에서분리된최초의 lignan 으로뇨, 담즙중에서 glucuronide 로서분비 steganacin: Steganotaenia araliaceae (Umbelliferae) 에서분리됨 - 항암활성 justicidin: Justica 속 R 1 C 3 R 2 C 3 3 C C C 2 C 3 3 C 3 3 C C 2 C 3 3 C 3 C C 3 C 3 schizandrin, R 1 =R 2 =C 3 biphenyldimethyldicarboxylate pinoresinol sesamin gomisin A, R 1 +R 2 =--C 2 - C 3 C 2 3 C C3 C 2 3 C 3 C enterodiol enterolactone 3 C 3 C steganacin justicidin A

116 podophyllotoxin: Phodophyllium 속식물, Juniferous virgiana 등에배당체로존재 - 항종양활성 3 C R C 3 3 C R C 3 3 C C 3 C 3 3 C C 3 C 3 podophyllotoxin, R=C 3 4'-demethylpodophyllotoxin, R= β-paltatin, R=C 3 α-paltatin, R= desoxypodophyllotoxin podophyllotoxone S 3 C C 3 3 C R C 3 3 C C 3 4'-demethylepipodophyllotoxin etoposide, R= etopophos, R=P teniposide

117 eolignan lignan의결합위치가 β-β' 위치 ( 또는 8-8') 가아닌화합물 magnolol, honokiol: 후박- neolignan, 자발운동억제, 중추성근이완, 항스트레스성궤양, 위액분비억제 futoenone: Piper kadzura ( 후추등 ) 의성분 kadsurenone: Piper futokadsura- PAF inhibitor asatone: Asarum속의화합물 3 C 3 C 3 C 3 C 3 C C 3 C 3 magnolol honokiol futoenone kadsurenone asatone

118 orlignan 탄소수가하나적은 (C17) 화합물 주로 Gymnosperm 중송백목즉낙우송과 (Taxodiaceae), 측백나무과 (Cupressaceae) 에서발견됨 sugiresionol hinokiresionl sugiresionl hinokiresinol

119 Lignan oligomer Phenylpropanoid가 3~5개결합한화합물 Sesquilignan (C27), dilignan (C36) 등 lithospermic acid- 자근 lappaol A- 우방자 lappaol F- 우방자 3 C 2 C C C 3 C 3 C C 2 C 3 C 3 3 C C 2 C 3 lithospermic acid lappaol A lappaol F

120 Lignoid- flavolignan, coumarolignan, xantholignan flavolignan-silybum mariaum: Compositae, milk thistle- 열매에함유된 1.5~3% 의 flavolignan을 silymarin이라칭함 - 간손상질환에사용 - 작용기전 : 독소의흡수저해, 항산화제및 scanvenger로작용 C 3 + C 3 silybin (diastereoisomeric pair) C 3 C 3 3 C isosilybin silychristin silydianin

121 Lignoid- flavolignan, coumarolignan, xantholignan coumarino-lignan: cleomiscosins A and B: Cleome viscosa 3 C 3 C 2 C C 2 C 3 cleomiscosin A cleomiscosin B C 3 xantholignoid: kielcorin: Kielmeyera coriacea C 3 kielcorin C 3

122 Biosynthesis of lignin

123 Lignin p-hydroxycinnamyl, coniferyl, sinapyl alcohol 등이 중합하여생성되는 polymer 목부의목화된조직에존재하는특이한물질 ( 목재의 20~30%) 세포벽에침착하여존재, 물에녹지않음 vanillin 의제조원료로사용 2 C 3 C C 3 C 2 C 3 3 C 2 C C 2 C 3 3 C C 3 식물체의따라구성 phenylpropanoid 가다름 Gymnosperm- coniferyl alcohol C 2 C 3 C 2 2 C C 3 Graminae- coniferyl alcohol, sinapyl alcohol, C 3 p-coumaryl alcohol + p-coumaric acid (5~10%) Angioaperm- conifery alcohol, sinapyl alcohol 3 C 2 C C 3 Structure of lignin

124 FLAVIDS Plant Pigments

125 PLAT PIGMETS Flavonoids and anthocyanins are conspicuous plant pigments in nature that are responsible for the beauty and splendor of flowers, fruits, fruit tree blossoms and of the autumn leaves. Flavones are responsible for the yellow and orange colors; and the anthocyanins are the source of red, violet and blue colors. These compounds occur mainly in higher plants and are less common in the lower orders. You don t find them in algae, fungi or bacteria. The flavonoids play a major role in attracting insects to feed and pollinate these plants. Some of them also have a bitter taste and repel harmful insects like caterpillars. Flavonoids are thought to be antioxidants, and play a major role in our diet, preventing the ravages of aging caused by free-radicals. These compound have their biosynthetic origin in both the skimic acid pathway and the acetogenin pathway - they are of hybrid origin.

126 shikimic acid pathway CoAS A different starter than acetyl-coa. ARIGEI found in grapefruit malonyl-coa 3x acetogenin pathway SCoA : internal Claisen and enolizations Michael addition MIXED-RIGI CMPUD A FLAVE flavones are yellow or orange pigments naringenin

127 Anthocyanin Flower Pigments

128 Anthocyanin Leaf Pigments Autumn Leaves In Spring and Summer chlorophyll (green) masks the anthocyanin colors.

129 ATCYAIDIS AD ATCYAIS R R R 2 ADP naringenin (R=) [] + R R Anthocyanins are red, violet or blue pigments. ATCYAIDIS pelargonidin (R=) cyanidin (R=) plant flower and leaf pigments cyanidin is blue pelargonidin is pink

130 Flavonoid C 6 -C 3 -C 6 단위로구성된화합물 C 3 의형태에따라 flavone, flavonol, flavonone, flavanonol, chalcone, aurone, anthocyanin B환의결합위치에따라 : isoflavonoid, neoflavonoid로분류 두분자의 flavone이중합된화합물을 biflavonoid라함 CoAS chain extension; acetate pathway with a cinnamoyl-coa starter group SCoA 3 x malonyl-coa SCoA ADP reductade SCoA C 2 aldol (stilbene synthase) Claisen (chalcone synthase) Claisen resveratrol (a stilbene) naringenin-chalcone (a chalcone) isoliquiritigenin (a chalcone) naringenin (a flavanone) liquiritigenin (a flavanone)

131 flavone flavonol flavanone flavanonol (=dihydroflavonol) flavonoid 골격 chalcone dihydrochalcone flavan-3-ol flavan-3,4-diol aurone anthocyanidin isoflavonoid neoflavonoid

132 1. Flavone, flavonol 현재분리된 flavonoid의약 80% 가이 group에속함 광범위하게분포 7 6 2' 4' 1 8 1' B A C B A C flavone flavonol apigenin, vitexin 거의모든식물에함유되어있음 luteolin, baicalin kaempferol scutellarein quercetin myricetin 2. Flavanone, dihydroflavonol flavone, flavonol의 2,3번에존재하는이중결합이없다 A C flavanone B naringenin hesperetin B A C dihydroflavonol alpinin

133 3. isoflavone 콩과식물에많이함유 phytoestrogen 으로불림, 주된 phytoalexin A C isoflavone B daidzein: Pueraria lobata ( 갈근 ) 및동속식물에함유, 진경작용 4. chalcone, dihydrochalcone, aurone chalcone-butein, carthamin ( 홍화 ) dihydrochalcone- phloretin-고혈당 aurone- sulphuretin 2 1 β 4 2' 1' α chalcone dihydrochalcone aurone

134 Phytoestrogen estradiol estrone estriol daidzein genistein coumestrol

135 5. anthocyanin 꽃, 식물의다양한생상원인물질 다양한색상은 anthocanidin 의종류, 결합한당의종류와수, 결합위치등과관련 세포액중에공존하는 Al, Fe, Mg 등의이온과착화합물형성에기여 6. biflavonoid flavone 2 분자가결합한구조, 나자식물들에함유 구성단위의 flavone 분자간의결합위치에따라 4 가지로분류 R 1 pelargonidin, R 1 =R 2 = R cyanidin, R 1 =, R 2 = 2 delphinidin, R 1 =R 2 = amentoflavone hinokiflavone cupressusflavone agathisflavone

136 7. neoflavone B ring 이 C-4 에결합된물질, 4-phenylcoumarin 이라고도함 brazillin, hematoxylin Stilbene resveratrol: 포도주의항암효과 neoflavonoid CoAS chain extension; acetate pathway with a cinnamoyl-coa starter group 3 x malonyl-coa C 2 SCoA aldol (stilbene synthase) resveratrol (a stilbene)

137 5. Mevalonate pathway C 2 hv 2 photosynthesis mono-, oligo-, polyosides 1) Monoterpenoids erythrose-4 phosphate glucose 2) Iridoids and Secoiridoids GLYCSIDES shikimate flavonoids anthocyanins tannins phospho-enol pyruvate phenols, quinones, polyacetylenes macrolides, fatty acids lipids PLYACETATES 3) Sesquiterpenoids 4) Diterpenoids SIKIMATES pyruvate acetyl CoA mevalonate 5) Sesterterpenoids cycle 6) Triterpenoids and Steroids cinnamates, lignans, coumarins quinones amino acid TERPEES AD STERLS proteins ALKALIDS essential oils, sesqui- and diterpenes, saponins, cardenolides carotenes

138 MEVALIC ACID PATWAY

139 Mevalonate pathway C mevalonic acid dimethylallyl PP (DMAPP) (C5) PP PP isopentenyl PP (IPP) (C5) emiterpenes (C5) IPP PP geranyl PP (GPP) (C10) Monoterpenes (C10) PP farnesyl PP (FPP) (C15) Sesquiterpenes (C15) IPP IPP PP geranylgeranyl PP (GGPP) (C20) Diterpenes (C20) PP geranylfarnesyl PP (GFPP) (C25) Sesterpenes (C25) 2 x FPP squalene Triterpenoids (C30) Steroids (C18-C30) 2 x GGPP phytoene Tetraterpenes (C40) carotenoids

140 Mevalonate pathway β-hydroxy-β-mehtylglutaryl-coa C SCoA SCoA mevalonic acid (MVA) Claisen reaction EnzS acetyl-coa reduction of aldehyde to alcohol ADP C SCoA SEnz Enzyme-bound acetyl group mevaldic acid stereospecific aldol reaction; also involves hydrolysis of acetyl-enzyme linkage C MG-CoA reductase MG-CoA SCoA ADP C SCoA mevaldic acid hemithioacetal + EnzS reduction of thioester to aldehyde via hemiacetal sequential phosphorylation ot the primary alcohol to a diphosphate 2 x ATP P ADP PP ATP -C R stereospecific allylic isomerization; equilibrium favors DMAPP 1 S PP isomerase PP ATP facilitates the decarboxylation-eliminatio n; the anticipated phosphorylation of the tertiary alcohol to make a better leaving group is apparently not involved isopentenyl PP (IPP) dimethylallyl PP (DMAPP)

141 TERE ARE TW CARBYL GRUPS I TE 2-UIT PLYKETIDE CAI EITER E CA REACT C C.. C 2 S CoA C C C 3 C 2 S CoA - C C 3 C S CoA LIEAR BRACED mevalonic acid C 3 C C 3 C C 2 C S CoA C 3 C C C C C2 2 SCoA C 2 C 2 C 2 C 2 C 2 C C SCoA PLYKETIDE CAIS TERPEES STERIDS ACETGEIS

142 MEVALIC ACID PATWAY FRMATI F MEVALIC ACID FRM ACETYL UITS 3 acetylcoa 3 C C 2 C C C 2 C SCoA SCoA ADP 3 C C C 2 C C 2 C SCoA SCoA :..: - 3 C C 2 C C C 2 C C C 2 C C C 2 C 2 SCoA ADP 3 C C 2 C C C 2 C SCoA mevalonic acid

143 The conversion of MGCoA into (3R)-MVA involves a two-step reduction of the thioester group to a primary alcohol, and provides an essentially irreversible and rate limiting transformation. Drug-mediated inhibition of this enzyme (MG-CoA reductase) can be used to regulate the biosynthesis of mevalonate and ultimately of the steroid cholesterol

144 MGCoA reductase Inhibitor Mevastatin is produced by cultures of Penicillium citrinum and P. brevicompactum, and was shown to be a reversible competitive inhibitor of MGCoA reductase, dramatically lowering sterol biosynthesis in mammalian cell cultures and animals, and reducing total and low density lipoprotein cholesterol levels.

145 The isopentenyl & 3,3-dimethylallyl pyrophosphate intermediates 3 C C 2 C C C 2 C 2 2 ATP ADP AMP P 3 C C 2 C C C 2 C 2 P P :B-Enz mevalonic acid Stereospecific allylic isomerization; equilibrium favours DMAPP P P C 2 C 3 C 3 3,3-dimethylallyl pyrophosphate (DMAPP) C Enz-B: 3 + P P C C isopentenyl pyrophosphate (IPP)

146 TERPEES? Terpenes 의정의와기본골격

147 TERPEES The Czech chemist Leopold Ruzicka ( born 1887) showed that many compounds found in nature were formed from multiples of five carbons arranged in the same pattern as an isoprene molecule. natural rubber head C tail. C C C C C C C isoprene isoprene unit C C e called these compounds terpenes.

148 JIIG ISPREE UITS ead-to-tail individual isoprene units join head-to-tail an extra bond Tail-to-Tail larger terpenoid units dimerize tail-to-tail The terms head-to-tail and tail-to-tail are often used to describe how the isoprene units are joined.

149 TERPEES CA BE SW T BE FRMED FRM ISPREE UITS head to tail limonene from lemon and orange peels diagram showing how two isoprene units combine to form the limonene skeleton

150 MTERPEES (C 10 ) C 2 geraniol rose and other flowers menthol peppermint camphor camphor tree α-pinene turpentine

151 SESQUITERPEES (C15) C 3 C 3 guaiazulene geranium oil C C 3 C 3 C 3 C 3 C 3 caryophyllene oil of cloves

152 C 3 C 3 C 3 C 3 cedrene cedar wood oil longifolene pine species

153 TRITERPEES (C30) C 3 C 3 C 3 C 3 C 3 C 3 C 3 ambrein ambergis TAIL-T-TAIL

154 STERIDS ARE TRITERPEES (C30) C 3 C 3 C 3 C 3 C 3 C 3 All steroids are triterpenes but their skeletons have been rearranged so that they can not be analyzed into isoprene units. rearrangements in this area

155 TETRATERPEE head-to-tail tail-to-tail head-to-tail β-carotene carrots

156 TERPEES의생합성기전 IPP 와 DMAPP 의중합기전 Terpenes 골격연장의일반적특성

157

158

159 CCATEATI F C5 (ISPREE) UITS C 3 C 3 C 2 C 3 PP C 2 PP C 2 EAD C 3 C5 :B C10 C 2 PP C5 PP TAIL C 2 C 2 PP PP C10 geranyl-pp C20 C15 C15 C 2 PP IPP C20 EAD-T-TAIL C 2 PP

160 C10, C15, C20 Vs. C30, C40 Class umber Isoprene of Carbons Units rigin MTERPEES C10 2 geranyl-pp x2 x2 SESQUITERPEES C15 3 farnesyl-pp DITERPEES C20 4 geranyl-geranyl-pp SESTERTERPEE C25 5 uncommon TRITERPEES C x (farnesyl-pp) TETRATERPEES C x (geranyl-geranyl-pp)

161 DIMERIZATI F C15 AD C20 UITS PP TAIL C 2 C 3 P C C 3 R rearrange P C 2 C TAIL 3 R R Enz-B: C dimerize P C 3 C 3 R : - C 3 C 3 P R AD AD + C C 3 C 3 R R R TAIL-T-TAIL R JIED SYMMETRICALLY TAIL-T-TAIL

162 CMM TERPEID SKELETS EMITERPEES TERPEES SESQUITERPEES C5 C10 C15 C20 DITERPEES TRITERPEES C30

163 Lower Terpenes Mono, Sesqui, Diterpenes

164 1. Monoterpenes GPP (generanyl pyrophosphate) 가전구체 (C10) 주로식물에서발견- 동물이나미생물에서도발견 식물정유의구성성분으로존재하기때문에수증기증류나용매추출에의해분리 구조 - acyclic (myrcane or 2,6-dimethyloctane, secoiridane) - monocyclic (e.g., p-methane, iridane) - bi- and tricyclic (e.g., carane, pinane, bornane, thuyane) myrcane p-menthane seco-iridane iridane carane pinene thujane bornane fenchane iso-camphane artemisane santolinane chrysanthemane lavandulane main structural classes of monoterpenoids

165 geranial geranium oil β-myrcene hops geraniol geranium oil neral lemon oil PP PP PP citronellol rose oil geranyl-pp (GPP) linalyl-pp (LPP) neryl-pp (PP) citronellal citronella oil α-terprneol linalool coriander oil nerol rose oil

166 PP ionize + PP - or methyl α-terpinyl cation LPP + + β-pinene ,2-alkyl shift ,2-alkyl shift α-pinene ADP borneol ADP + camphene fenchone fenchol camphor

167 camphor: 녹나무 (Cinnamomun camphor) 에서얻어진것, 국소자극으로신경통, 염증, 타박상등에대한찰제, 중추자극작용 menthol: 박하 (Mentha arvensis) 또는양박하 (Mentha piperita) 의정유중에함유, 피부에냉감작용, 약한마취작용, 진통, 제양작용 paeoniflorin: 적작약 (Paeonia lactiflora) 에서얻어낸 monoterpene glycoside의 benzoate, 진통, 진경, 항염증 limonene: lemon의정유성분, 진정, 중추억제작용 fenchon: 회향 (Foeniculum vulgare), 딱정벌레류에대해서살충작용 1) acyclic monoterpene 2) monocyclic monoterpene 3) bicyclic monoterpene citronellol (rose oil) geraniol (geranium oil) nerol (rose oil) limonene α-terpineol (-)-menthol (levomenthol) thujone fenchol fenchone β-myrcene (hops) neral (E-citral) (lemon oil) geranial (Z-citral) (lemon oil) thymol charvacrol p-cymene cineol camphor α-pinene

168 Irregular monoterpene GPP 를전구체로하지않고 2 분자의 DMAPP 가축합하여생성되는 monoterpenes - pyrethrins: 제충국 (Chrysanthemum cineraiefolium) 등의꽃에함유 - pyrethrins, cinerin, jasmolin - 유용한살충성분 PP electrophilic addition giving tertiary cation PP PP loss of proton via cyclopropyl ring formation hydrolysis of phosphate ester; oxidation of alcohol to acid PP C chrysanthemic acid cf. regular monoterpene skeleton R 1 R 2 C chrysanthemic acid C 3 CC pyrethric acid pyrenthrin I, R 1 =C 3, R 2 =C=C 2 pyrenthrin II, R 1 =CC 3, R 2 =C=C 2 cinerin I, R 1 =C 3, R 2 =C 3 cinerin II, R 1 =CC 3, R 2 =C 3 jasmolin I, R 1 =C 3, R 3 =C 2 C 3 jasmolin II, R 1 =CC 3, R 2 =C 2 C 3 pyrethrolone cinerolone jasmolone teramethrin bioresmethrin Cl Cl R permethrin, R= cypermethrin, R=C

169 2. Iridoids and Secoiridoids iridoid: cyclopentane ring이있음 GPP로부터생합성됨 쌍자엽식물에주로분포됨 기본핵 iridoid secoiridoid geraniol via hydroxylation and oxidation C C iridodial (keto form) cyclization formulated as initiated by electrophilic addition utilizing the unsaturated carbonyl, terminated by addition of hydride; the Schiff base-assisted mechanism shown below is more realistic hemiacetal formation C iridodial (enol form) iridodial (hemiacetal form) =

170 biosynthesis of loganin and secologanin * PP * * GPP * * nerol * * C * C C C C * C C* *C 1/2 * Glc * C* * C*C 3 1/2 * Glc C CC 3 Glc loganin secologanin

171 harpagoside- 현삼, 소염진통작용 catalpol- 지황, 혈압강하작용 linaroside- 운란, 완화 ( 緩和 ) 작용 geniposide- 치자, 완화, 이담, 지혈, 소염, 강장해독, 해열 villoside: 패장 loganin, gentioside: 수채엽 syringopicroside: 야정향 valtrate, dehydrovaltrate: 길초근, 진정, 불면증완화 muzenide: 여정실 picroside I, II, III: 호황련 CC 3 CC 3 C 2-Glc R R Glc harpagoside, R=t-cinnamoyl Glc loganin 2 C R genipin, R= geniposide, R=Glc Cl Glc linarioside villoside 2 C Glc catalpol, R= catalposide, R=p-hydroxybenzoyl Ac Ac Glc Glc CC 3 Glc valtrate dihydrovaltrate syringopicroside aucubin gardenoside

172 Secoiridoid: iridoid의 7,8번탄소사이가개환된상태 Gentianaceae, Rubiaceae, leaceae, Cornaceae에많이존재 secologanin: 인동과식물등에존재, 모든 secoiridoid의중간체 monoterpene indole alkaloid의생합성에중요한전구체임 용담, 겐티아나, 당약- gentiopicroside, swertmarin, sweroside, amorogentin Glc R Glc R Ac C 2 Ac Glc gentiopicroside swertiamarin, R= sweroside, R= amarogentin trifloroside R=CC 3 benzoyltrifloroside R= C

173 3. Sesquiterpenes 3개의 isoprene unit로이루어져있는 FPP (farnesyl pyrophosphate) 를공통의전구체로하여생합성되는화합물 E, E-FPP 혹은 E, Z-FPP의 pyrophosphate group이분자내 2중결합의관여로탈리해서환상 carbonium ion을생성 - carbonium ion 은더욱분자내의다른 2 중결합의공격 geranyl PP (GPP) PP 을받아새로운 ring을형성하기도하고, 또한인접한수소원자의이동 (hydride shift) 및 alkyl group 의이동 (Wagner-Meerwein rearrangement) 등을거쳐서다른 allylic cation R S PP electrophilic addition giving tertiary cation carbonium ion 이된다. - carbonium ion 은최종적으로탈 proton 화되거나물분 자의공격에의해각각 olefin 또는 carbinol 이된다. R S PP stereospecific loss of proton PP farnesyl PP (FPP) FPP 의생성경로

174 E E, E-FPP E PP E Z PP E, Z-FPP PP nerolidyl PP

175 Sesquiterpene 의생합성 E E germacryl cation guaiyl cation matricin E,E-farnesyl cation humulyl cation humulene eudesmyl cation α-santonin a bisabolyl cation caryophyllyl cation E a a Z b E, Z-farnesyl cation b carotyl cation W-M 1,3-hybride shift b cis-germacryl cation cadinyl cation artemisinin cis-humulyl cation

176 1) acyclic sesquiterpene 곤충, 해양식물, 식물등에서얻어짐 juvenile hormone (J)-곤충의유약형질유지 farnesol, (+)-nerolidol, farnesene faranal- 파라오개미의분비액에존재하는방어물질 ipomenamarone-ipomoea batatas ( 고구마 ) 의 phytoalexin R 3 R 2 R 1 CC 3 C juvenile hormone (J) J-, R 1 =R 2 =R 3 =C 2 5 J-I, R 1 =C 3, R 2 =, R 3 = J-II, R 1 =R 2 =C 3, R 3 =C 2 5 J-III, R 1 =R 2 =R 3 =C 3 ipomeamarone faranal

177 Phytoalexin Phytoalexins are low molecular weight, lipophilic, antimicrobial compounds that accumulate rapidly around sites of incompatible pathogen infections and in response to an extensive array of biotic and abiotic elicitors (Smith, C.J. (1996). Accumulation of phytoalexins: Defense mechanism and stimulus response system. ew Phytol. 132, 1-45.) Examples of Stress-Induced Phenylpropanoids

178 Phytoalexin 식물이외부침입 (fungi, bacteria, virus) 에대항하기위하여합성하는물질 Solanaceae 에서만 40 여종분리되었음 Solanaceae- sesquiterpene phytoalexin ipomeamarone ( 고구마 ), rishitin ( 감자 ), debneyol ( 담배 ), capsidiol ( 고추 ) Leguminosae- isoflavonoids camalexin ( 애기장대, Arabidopsis thaliana) 6-methoxymellein: isocoumarin, 당근의 phytoalexin

179 2) humulene & caryophyllene E, E-FPP의말단위치 (C10) 의이중결합이관여하여 pyrophsphate 가떨어져나가면서 C11 의 carbonium ion, humuyl cation을거쳐서생성되는화합물 humulene- 홉프 (umulus lupulus) 의정유 caryophyllene- Myrtaceae, 정향 (Syzygium aromatica) 의꽃봉오리정유면화 (Gossypium hirsuta) 의꽃봉오리정유 E E E,E-farnesyl cation humulyl cation caryophyllyl cation humulene caryophyllene

180 3) Germacrane E, E-FPP의말단위치 (C10) 의이중결합에의해 C1~C10 위치사이에서 ring을형성할때환상 carbonium ion (C10) 을거쳐서 germacrene-a, hedycaroyl 등이생성되는생합성과 정을거치는화합물 α-exomethylene-γ-lactone ring을가진유도체는항종양활성, 식물성장억제 germacrene-a, hedycaroyl, periplanone B, heliangine, pyrethrosine-제충국 (Chrysanthemum cinerariaefolium) 에서얻어진물질- 식물성장억제 costunolide- 목향 (Saussurea lappa)- 항염증, 세포독성 E E E,E-farnesyl cation germacryl cation Ac germacrene A costunolide pyrethrosine

181 4) Elemane Germacradiene이 Cope rearrangement를거쳐서생성 saussurea lactone vernolepin- Vernomia hymenolepsis의잎에서단리된 elemane형, sesquiterpene dilactone- 강한항종양활성 hydycaryol elemol dihydrocostunolide saussurea lactone elemene vernolepin vernomenin

182 5) Eudesmane Germacradiene이 transannular cyclization을거쳐 bicyclic compound 형성 atractylon: 창출백출, 건위작용 alantolactone: 토목향 (Inula helenium), 구충작용 petasin, isopetasin: 머위, 진경작용 santonin: Artemisia cina ( 시나화 ), A. maritima- 회충구제 capsidiol: 고추의 phytoalexin - hydycaryol β-eudesmol atractylon (-)-α-santonin alantolactone R petasin, R=angeloyl R isopetasin, R=angeloyl

183 6) Guaiane guaiane- perhydroazulene 골격을지님 chrysanthmin A, euparotin: α-exomethylene-γ-lactone ring을포함하고있어, 세포독성, 항종양활성, 식물성장저해효능이있음 pseudoguaiane- guiane의 methyl group이 1, 2-rearrangement 되어생성 ambrosic acid: Ambrosia artemisiaefolia ( 돼지풀 ), allergy 유발 helenalin: elenuim autumnale, antibacterial, antitumor Ang C chrysanthemin A euparotin ambrosic acid helenalin guaiane pseudoguaiane

184 7) Cadinane E,Z-FPP의 ring이닫히고 1,3 위치의 가이동하면서생성 gossypol- atropoisomer,gossypium spp의종자, 잎, 줄기등에서발견되는황색색소 (+)-gossypol- antitumor, antiviral activity (-)-gossypol- contraceptive (male contraceptive, altering sperm maturation) C C gossypol α-cadinol C C C C (+)-gossypol (-)-gossypol

185 8) elminthosporal 및 Tutin Cadinan 골격이계속 cyclization 되면서 copabornyl cation을중간체로하여생성됨 helminthsporal: elminthsporal sativum ( 소맥반점병균 ) 의독소 tutin, coriamyrtin: Coriaria spp에서분리된독성물질로 GABA antagonist R R C tutin, R= coriamyrtin, R= helminthosporal, R=C helminthosporol, R=

186 9) Bisabolane 및그유도체 E,Z-FPP의 pyrophosphate가분리되면서 bisabolyl cation 중간체를형성하고이후생합성과정을통해 bisabolane이생성된다. juvabione: Abies balsamea의목부에함유 sirenin: Allomyces의 sex pheromene fumagillin: Aspergillus fumigatus의항생물질 E Z b a = E,Z-farnesyl cation bisabolyl cation bisabolol CC 3 C 3 C juvabione sirenin fumagillin

187 10) Cuparane 및 Trichothecane bisabolyl cation cuparyl cation-a cuparyl cation-b helicobasidin: elicobasidium mompa 의자색소 trichothecene: Tricothecium roseum 의 antiviral agent, anti-fungal, anti tumor. 11) Mono- 및 bicyclofarnesane 형 sesquiterpene FPP 의 pyrophosphate 가 ring closure 에직접관여하지않고말단의 ring closure 에관여 (+)-abscisic acid: Plant growth regulator warbuganal: Spodoptera exempta 에대한 feeding deterrant

188 artemisinin(=qinghaosu) sesquiterpene lactone, peroxide linkage(=endoperoxide) Artemisia annua, 함량 : 0.06~0.16% antimalaria cadinyl cation 을거쳐서생합성 C artemisinic acid arteannuin B artemistene = artemisinin R C C artemether, R=C 3 arteether, R=C 2 C 3 artelinic acid artesunic acid yingzhaosu C yingzahaosu A

189 4. Diterpenoids FPP + IPP = GGPP -diterpenes (C20) GGPP(geranylgeranylpyrophosphate) 로부터생합성되는 C20의화합물 화학구조는복잡하나거의대부분이환상 (cyclic) 을이룬다 식물계에약 1000 종이알려져있는데, 균대사산물, 해양생물, 병정개미의분비물에서도발견된다 labdane clerodane pimarane isopimarane abietane podocarpane totarane cassane kaurane beyerane gibberellane atisane aconane taxane diterpene 의골격

190 1) acyclic diterpenes phytol: 식물계의녹색색소인 chlorophyll 분자의 porphyrin 부의 ester 로서존재 vitamin A: lipophlic vitamin, 상어, 대구간유에많다. 망막색소와포유동물의생 자에중요한역할을한다. 화장품에도사용 Shikimate pathway

191 2) cyclic diterpenes (I) columbin: 칼룸바근, 고미강장작용 abietic acid: terepin oil, rosin, 효모성장촉진제로사용 gibberellin: 식물성장호르몬 stevioside: Stevia rebaudiane ( 스테비아엽 ) 에함유감미료 ( 설탕의 150배 ) pimaric acid: pimarane계수지산, Pinus maritima의 rosin에서얻어짐 forskolin: Coleus forskolii에서분리된혈압강하제 (adenylate cyclase를활성화시켜 c-amp의합성촉진 ) C (-)-abietic acid columbin CGlc stevioside Glc 2 Glc C C C Ac gibberellic acid GA 3 pimaric acid forskolin

192 cyclic diterpenes (II) ginkgolide- 은행잎, bilobalide( sesquiterpene, 30~40%), ginkgolide A (30%), PAF antagonist phorbol ester: Croton tiglium ( 파두 ), 발암성분 diterpene alkaloids: 구조상 diterpene의질소유도체 (aconitine 등 ) 3 C taxol: Taxus brevifolia ( 주목과 ), 항종양활성 R 2 C(C 3 ) 3 R 3 R 1 R 1 R 2 C 2 C 3 C 3 CC 6 5 R 1 R 2 CC 3 C 3 3 C ginkgolide A, R 1 =, R 2 =, R 3 =, ginkgolide B, R 1 =, R 2 =, R 3 =, ginkgolide C, R 1 =, R 2 =, R 3 = ginkgolide J, R 1 =, R 2 =, R 3 = phorbol ester A 1, R 1 =myristyl, R 2 =acetyl phorbol ester A 2, R 1 =caproyl, R 2 =acetyl phorbol ester B 1, R 1 =methylbutyryl, R 2 =lauryl phorbol ester B 2, R 1 =methylbutyryl, R 2 =caproyl aconitine, R 1 =C 2 5, R 2 = mesaconitine, R 1 =C 3, R 2 = hypaconitine, R 1 =C 3, R 2 = bilobalide C(C 3 ) 3

193 taxol (paclitaxel) Taxus brevifolia ( 주목과 ), 1967년에분리 (1971년보고 ), 항종양활성, 1993년에시판 100년된나무에서수피 3Kg 확보가능하고이로부터 300mg 확보가능, 치료과정에 2g 필요, 1Kg을얻기위해약 7 ton의나무가필요 ovarian, breast cancers, non small lung cancer, head and neck cancer Taxol (paclitaxel), taxotere (docetaxel) 세포분열시 microtuble에결합하여안정화시켜 depolymerization억제-세포분열억제 block cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication Ac L-Phe acetyl-coa taxadiene 10-deacetylbaccatin III semisynthesis L-Phe paclitaxel (taxol) L-Phe acetyl-coa Ac docetaxel (taxotere)

194 TAXL Phe PP Phe GGPP C 3 paclitaxel (taxol) Pacific Yew (bark) acetylcoa (+) yr-old trees = 1 g Used clinically in treatment of breast, ovarian, lung, head, neck cancers. C 3 acetylcoa taxadiene C 3 many steps: oxidations, esterification Phe

195 Steroid/Triterpene 의생합성기전

196 STERIDS C D Compounds with the four-ring pattern A-B-C-D are called steroids. A B Most steroids also have a side chain on ring D and angular methyl groups at the junctions of rings A/B and C/D. Frequently there is an oxygenated group at C3 (arrow)... in this section we will see how steroids arise

197 FRMATI F SQUALEE C5 C 3 IPP :B C10 C 2 PP PP C5 C 2 C 2 PP DMAPP PP C5 C15 + C15 C15 PP PP C 2 C 2 C 2 PP squalene C30 Squalene is the precursor of all steroids in both plants and animals.

198 SQUALEE FLDIG CFRMATI CAIR-BAT-CAIR-BAT FLDIG CAIR BAT BAT TAIL CAIR Squalene has to be folded in a specific fashion when it binds to the cyclase enzyme that converts it to a steroid. This folding is called a chair-boat-chair-boat conformation. If squalene cannot adopt this conformation, it cannot form a steroid and will form some other type of triterpene...

199 CAIR-BAT-CAIR-BAT FLDIG CAIR BAT BAT TAIL CAIR

200 FRMATI F LASTERL MAMMALS.. action of a mammalian cyclase enzyme - a remarkable biosynthetic sequence

201 EPXIDATI F SQUALEE BY A FLAVPRTEI MXYGEASE flavoprotein ADP squalene Enz-B squalene-2,3-epoxide enzyme-catalyzed ring opening CARBCATI tertiary! +

202 CYCLIZATI F SQUALEE FRMATI F A STERID - LASTERL (MAMMALS) squalene elimination B: C 3 + C 3 C 3 3 C C 3 9 C 3 + Gray groups rearrange by 1,2-shifts 3 C C 3 C C 3 C 3 C 3 lanosterol The proton at C9 is lost in an elimination = double bond from C8 to C9

203 RIG CLSURES All the orbitals are perfectly aligned for these internal polymerizations.

204 MAMMALS I TREE DIMESIS C 3 C 3 C 3 C 3 C 3 R + C 3 ELIMIATI T FRM A DUBLE BD :B CARBCATI REARRAGEMETS SKELET (WAGER-MEERWEI)

205 C 3 :B-Enz C 3 C C C 3 ATER C 3 VIEW C 3 C 3 3 C 3 C

206 ALL TER STERIDS I MAMMALS ARE DERIVED FRM LASTERL 3 C 3 C cholesterol C 3 C 3 C 3 C 3 C 3 3 C C 3 C 3 lanosterol estrone pregnenolone C 3 C C C 3 3 estradiol C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 corticosterone progesterone testosterone

207 C 3 C squalene = 14 C RADIACTIVE LABELLIG EXPERIMET lanosterol Agrees perfectly with the biosynthetic sequence. cholesterol

208 FRMATI F CYCLARTEL PLATS

209 CYCLIZATI F SQUALEE FRMATI F A STERID - CYCLARTEL (PLATS) squalene B: C 3 + C 2 C C C C 3 2 C 3 C C 3 + C 3 C 3 C 3 cycloartenol The proton at C9 migrates to C8, a proton is lost from the methyl at C10 forming a cyclopropane ring.

210 PLATS C 3 C 2 C 3 C 3 C 3 :B FRMATI F CYCLPRPAE RIG CARBCATI REARRAGEMETS SKELET (WAGER-MEERWEI) R + C 3

211 SME TER PLAT STERIDS sigmasterol (soy beans) diosgenin (mexican yams) Used by Marker to synthesize the first birth control pills. SYTEX 3 C C C digitoxigenin (Digitalis spp, foxglove) norethindrone

212 β-sitosterol wheat germ oil, corn oil 3 C 3 C C strophanthidin Strophanthus spp sapogenin, arrow poison C 3 ouabain Strophanthus spp sapogenin, arrow poison

213 TER FLDIGS F SQUALEE TER STERIDS TER TRITERPEIDS

214 TER TRITERPEIDS FRM SQUALEE The particular cyclase enzyme in a given plant can bring about variations in the folding of squalene, resulting in different types of natural products being formed. ot every plant cyclizes squalene to steroids. There is a hugh variety of other triterpenoids found in different plant sources, each of which act on squalene differently.

215 CAIR-CAIR CAIR-CAIR CAIR-CAIR CAIR-CAIR + + attack from both ends α-onocerin

216 CAIR-CAIR CAIR-CAIR-BAT + :.. + dammarenediols

217 igher TERPEES

218 1. Triterpene and Steroids (2 x FPP) FPP + FPP = Squalene으로부터생합성되는탄소수 30개를기본으로하는화합물 약 4000개분리되었음 대체로 2,3-oxidosqualene을경유해서생성 saponin: triterpene 및 steroid 는유리또는 ester 형으로존재하는경우와배당체로존재하는경우 로대별할수있는데후자를 saponin이라한다. 물을가하여흔들면지속적인거품을내고계면활성작용이있음 혈액중에서 cholesterol과난용성착화합물을형성하고적혈구를용혈시키는작용이있다 약리작용 : 진해, 거담, 항염증, 중추억제, 항피로, 항궤양, 지질대사촉진, cholesterol 대사촉진, 핵산및단백질의합성촉진, 세포수명연장등의작용이인정됨 2 x FPP squalene 2,3-oxidosqualene chair-boat-chair-boat chair-chair-chair-boat steroid lanosterol ( 동물 ) cycloartenol ( 식물 ) prostane, lanostane, cycloartane, cucurbitane triterpenoid dammarane, euphane, lupane, oleanane, ursane, hopane, limonoid, quassinoid

219 배당체 (Glycoside) glycoside aglycone + 당 R R α-glucoside (axial) β-glucoside (equatorial)

220 FPP squalene synthase PP * * FPP allylic cation * * PP loss of proton with formation of cyclopropane ring * PP loss of diphosphate gives primary cation * * presqualene PP cation quenched by attack of hydride * W-M 1,2-alkyl shift * * * bond cleavage produces alkene and favorable allylic cation 1,2-alkyl shift generates more favorable secondary cation and less-strained cyclobutane ring * * squalene squalene 의생성

221 Triterpene 화합물의생합성 obakunone 3 C C 3 quassin C + squalene-2,3-oxide ursolic acid dammarenyl cation C dammarenediol betulinic acid C () protopanaxadiol (protopanaxatriol) glycyrrhetic acid β-amyrin C 2 C C 2 platycodigenin oleanolic acid C C 2 saikogenin A

222 1)Triterpene 계 saponin (1) Tetracyclic triterpene: 환 4개 측쇄의결합형태에따른분류 prostane, lanostane, dammarane, euphane, cycloartane, curcurbitane (2) Pentacyclic triterpene: 환 5개 측쇄의결합형태에따른분류 ursane, oleanane, hopane, lupane Ac lanosterol cycloartenol cucurbitacin E euphol β-amyrin oleananes α-amyrin ursanes fiedelin (friedelane) taraxasterol (taraxastanes)

223 1-1. Prostane 계 triterpene 택사 - alisol A monoacetate: 혈장과간장의 cholesterol 량저하 prostane R R Ac alisol A, R= alisol A acetate, R=AC alisol B, R= alisol B monoacetate, R=Ac alisol C monoacetate

224 1-2. Lanostane 계 triterpene lanosterol: 양모지 eburicoic acid: 복령 (Poria cocos) lanosterol 30 C lanostane R eburicoic acid, R= tumulosic acid, R=

225 1-3. Cycloartane 계 triterpene- B ring 에 cyclopropane ring 이있음 cimigenol, cimogol, cimicifugoside: 승마 - 여성의갱년기장애치료보조제 astragalosides: 황기 γ-oryzanol 24 R 2 15 Ac R 1 Xyl- 15R, 24S, cimigenol, R 1 =, R 2 = S, 24R, cimigol, R 1 =, R 2 = 15R, 24S, 25--methylcimigenol, R 1 =, R 2 =C 3 cimigenyl arabinoside, R 1 =Ara, R 2 = cmingenul xyloside, R 1 =Xyl, R 2 = cimicifugoside cycloartane 3 C R 1 Xyl R 2 astragaloside III, R 1 =Glc, R 2 = astragaloside IV, R 1 =, R 2 =Glc astragaloside VI, R 1 =Glc, R 2 =Glc γ-oryzanol

226 1-4. Dammarane계 triterpene saponin 인삼 saponin 20(S)-protopanaxadiol- 중추억제및정신안정, 6번위치에 -가없다, 3,20번이 glycoside인 bisdesmoside, 20(S)-protopanaxatriol- 중추흥분작용, 6번위치, 3번위치에당이없다, mono- or bisdesmoside 산조인의 saponin R 2 R 1 20 (S)-protopanaxadiol 20(S)-protopanaxadiol ginsenoside-r a1 ginsenoside-r a2 ginsenoside-r b1 ginsenoside-r b2 ginsenoside-r b3 ginsenoside-r c ginsenoside-r d R 1 Glc 2 Glc- Glc 2 Glc- Glc 2 Glc- Glc 2 Glc- Glc 2 Glc- Glc 2 Glc- R 2 Xyl 4 Ara(p) 6 Glc Xyl 2 Ara(f) 6 Glc- Glc 6 Glc Ara(p) 6 Glc Xyl 6 Glc Ara(f) 6 Glc Glc 2 Glc- Glc dammarane R 1 R 2 20(S)-protopanaxatriol ginsenoside-r e ginsenoside-r f ginsenoside-r g1 ginsenoside-r g2 20 S-glucoginsenoside-Rf ginsenoside-r h1 R 1 Rha 2 Glc-- Glc 2 Glc-- Glc-- Rha 2 Glc-- R 2 Glc 2 Glc-- Glc-- Glc- Glc- Glc- 20 (S)-protopanaxatriol

227 Ginseng Saponins Ginsenosides Secondary aglycones G-Rb 1, GRb 2 G-Rb 3, G-Rc, G-Rd Acidic hydrolysis panaxadiol G-Re, GRf, G-glc-Rf, G-Rg 1, G-Rg 2 Acidic hydrolysis panaxatriol Genuine aglycones artifacts + 20 R R protopanaxadiol, R= protopanaxatriol, R= panaxadiol, R= panaxatriol, R=

228 1-5. opane lupane type과 germinal methyl group의위치가다르다 함유생약 : 모근 (Imperata cyclindrica)- arundoin, fernenol 1-6. Lupane 함유생약 : 섬오갈피 (Acanthopanax koreamum)- koreanoside, lupeol, betulin hopane lupane R arundoin, R=C 3 fernenol, R=

229 1-7. Cucurbitane계 triterpene 박과 (Cucurbitaceae) 식물에존재 cucurbitacin E: 고미, 제암효과, 준하효과 괄루근 R R curcubiracin B : R=CC 3 curcubitacin D : R= 23,24-dehydrocurcubitacin B : R=CC 3 23,24-dehydrocurcubitacin D : R= cucurbitane Ac curcurbitacin E

230 1-8. leanane계 triterpene 약리작용에따른분류 : 거담작용, 소염작용 거담작용- 세네가, 원지, 길경 소염작용- 시호 (saikosaponins), 감초 (glycyrrhizin), 목통 (akebioside st), 위령선 (clematosides) R 3 Glc C C 2 C C Fuc Rha Xyl Gal 3 3 R 1 R 2 Glc C R 1 R 3 C 2 Fuc 4 Rha 3 Xyl R 2 C 2 4 C 3 C 3 C oleanane senegin II, R 1 =, R 2 =, R 3 =C 3 senegin III, R 1 =Rha, R 2 =, R 3 = senegin IV, R 1 =Rha, R 2 =Rha, R 3 = C 2 4 Ara Rha Xyl Api 3 2 R 4 R 3 3 onjisaponin E, R 1 =, R 2 =, R 3 =Gal onjisaponin F, R 1 =Api, R 2 =Ara,R 3 = onjisaponin G, R 1 =Api, R 2 =, R 3 = R 2 R 1 C 2 platycodin A platycodin C platycodin D platycodin D 2 polygalacin D polygalacin D 2 R 1 C 2 C 2 C 2 C 2 C 3 C 3 R 2 Glc Glc Glc 3 Glc-Glc 3 Glc Glc-Glc R 3 Ac R 4 Ac

231 1-9. Ursane 계 triterpene ziyu-glycoside: 지유 (Sanguisorba officinalis, 오이풀 ), 지혈, 대장염 asiaticoside: 적설초 (Centalla asiaticoside, 병풀 ), 상처치유 ursane R 1 R 2 asiatic acid, R 1 =, R 2 = asiaticoside, R 1 =, R 2 =Glc 6 Glc 4 Rha madecassic acid, R 1 =, R 2 = madecassic acid, R 2 =Glc 6 Glc 4 Rha R 1 R 2 ziyu-glycoside I, R 1 =Ara, R 2 = ziyu-glycoside II, R 1 =Ara, R 2 =Glc

232 1-10. limonoid Rutaceae의대표적인고미성분, Citrus속에많다 구조적특징 : furan ring이있고, A ring이개환된상태 limonin ( 등피 ), obakunone ( 황백 ) quassinoid 소태나무과 (Simarobaceae) 에국한, quassin( 고목 ) C 3 3 C limonin obakunone quassin

233 2. Steroids Cyclopentanoperhydrophenanthrene frame 및생합성적으로이로부터유래한화합물군의총칭 동식물중에넓게분포, hormone, vitamin등의생리활성을가짐 steroid saponin - 쌍자엽식물 : Solanaceae, Leguminosae. Zygophyllaceae, Scrophulariaceae, Apocyaceae - 단자엽식물 : Liliaceae, Dioscoreaceae, Amaryllidaceae, Graminae, Palmae C D A B cholesterol Steroid numbering

234 Steroids conversion of lanosterol to cholesterol lanosterol cholesterol 1) reduction of C-24 double bond 2) demethylation of at C-14, C-4 3) shift of double bond in B ring

235 Steroids 기본골격 estrane androstane pregnane cholestane cholane ergostane stigmastane spirostane cardenolide bufadienolide

236 trans-decalin cis-decalin A B C D A B C D A B C D stereochemistry of steroid A all-trans A A/B cis A A/B cis, C/D cis A B C D A/B with 5-unsaturation A B C D A/B with 4-unsaturation A B C D A ring aromatic

237 Steroids 정색반응 : Liebermann-Buchard, Salkowiski reaction positive cholesterol: 척추동물의대표적 sterol, 거의모든세포종에서발견됨 β-sitosterol: 식물중에서발견되는 sterol의대표, stigmasterol, campesterol과함께함유되어있음 fucosterol: 해조류의대표적인 sterol ergosterol: 균류에포함된대표 sterol ergosterol lumisterol, tachysterol ergocalciferol brassinolide: Brassica napus의화분에서단리된식물성장촉진인자

238 Steroid 화합물의생합성 + squalene-2,3-oxide protosteryl cation lanosterol cycloartenol Ac cinobufogenin pregnenolone cholesterol diosgenin (25R, 5,6) acetyl CoA digitoxigenin campesterol β-sitosterol stigmasterol

239 Steroidal saponin Spirostane-type aglycone 에따른분류 - Tigogenin 형, Sarsapogenin 형, Diosgenin 형 - 5α, A/B ring: trans (tigogenin, digitogenin) - 5β, A/B ring: cis (sarsapogenin, smiliagenin,) - 5,6 double bond는남아있거나 (diosgenin) tigogenin (25R, -5α), A/B trans - 25 번탄소의 configuration 만다름 - neosapogenin: 25 S, axial methyl group - isoneosapogenin: 25 R, equatorial methyl group - B/C and C/D ring: trans - C-20: S, Sarsapogenin (25S, -5β), A/B cis - C-22: R diosgenin (25R, 5,6)

240 tigogenin (25R, -5α), A/B trans sarsapogenin diosgenin (25S, -5β), A/B cis (25R, 5,6) S 형 furostane 형 25,27 형

241 Steroidal saponin 1) diosgenin형 dioscin: 산약 R 1 ophiophogonin A-D: 맥문동 R 2 ophiopogonin A R 1 R 2 2) digitogenin형 digitonin, gitonin, togonin: 디기탈리스 Rha 2 Fuc-- Ac 3) sarsapoginin형 timogenin: 지모 parillin, sarsaparilloside Gal- 2 R timosaponin A-I, R= timosaponin A-III, R=Glc Rha 4 Glc 2 Rha smilax saponin B C 3 Glc 4 3 Xyl Gal Gal 3 2 Glc Glc R digitonin (aglycone: digitogenin) F-gitonin, R= desglactotigonin, R=

242 furostane 형 saponin 의 spirostan 형으로의변환 Rha 4 Glc 2 Rha protodioscin Glc β-glucosidase Rha 4 Glc 2 Rha dioscin

243 Bile acids 담즙산 (Bile acids) 의특징 C24 cholane skeleton cis-fusion of A/B rings C 2 a C5-carboxylic acid side-chain 3α- and 7α-hydroxyls C 2 C glycine sodium glycocholate 2 taurine S 3 3 S 3 a sodium taurocholate C C ursodeoxycholic acid dehydrocholic acid

244 Cardiac glycoside ( 강심배당체 ) 특징 C17 측쇄에 lactone 겹합 cardenolide (C23)-C17에 butenyl lactone bufadienolide (C24)-C17에 coumalin 환축합 lactone ring이 β-위치결합 C14의 가 β-위치로결합 C/D ring 이 cis 17 D A B 14 cardenolide-digitoxigenin 17 C 14 bufadienolide-hellebrigenin A/B ring 도 cis: 생리활성이크다 2,6-dideoxy sugar(digitoxose) or deoxysugar 가많다 sugar 는 3-β 로결합 characteristic features of cardiac glycosides: - cis-fused A/B and C/D - 14β-hydroxyl - unsaturated lactone at C-17β - sugar residues on 3β-hydroxyl 작용기전 강심배당체가 a +, K + -ATPase 저해 세포내에 K + 감소, a + 증가 a + 와 K + 간의교환기전작용으로세포내 Ca 2+ 증가 심근수축

245 Digitalis - a-k ATPase 작용기전강심배당체가 a +, K + -ATPase 저해 세포내에 K + 감소, a + 증가 a + 와 K + 간의교환기전작용으로세포내 Ca 2+ 증가 심근수축 a + K + a + Ca ++ Ca ++ K + a + Myofilaments CTRACTILITY

246 함유생약 생약명기원식물명성분응용 digitoxin, gitoxin, ditaloxin, 울혈성심부전디기탈리스 Digitalis purpurea purpurea glycoside A,B 강심이뇨약 털디기탈리스 Digitalis lanata lanatoside A, B, C: 강심효과가 digitalis 보다빠르고축적이낮다. 강심이뇨 스트로판치자 Strophanthus kombe K-strophanthin-β, G-strophanthin(ouabain), cymarin 심기능부전증 협심증 영란 Convallaria keiskei convallotoxin 복수초 Adonis amurensis cymarin 이뇨약 해총 Urginea scilla 백색해총 : scillaren A, scilliglycoside 적색해총 : scillirose, scillaren A, scillirubroside 강심제 살서제 섬수 ( 동물 ) Bufo bufo gargorizans Bufotoxin, vulgarobufotoxin 강심이뇨 정색반응 Keller-Killiani reaction- deoxysugar Kedde reaction-cardenolide 의 α,β-unsaturated γ-lactone

247 Cardenolide (C23)- digitalis-strophanthus type 디기탈리스강심배당체 : Digitalis purpurea R Dig Dig Dig R 2 R 1 digitoxin gitoxin ditaloxin purpurea glycoside A purpurea glycoside B glucogitaloxin R 1 -C -C R 2 Glc Glc Glc C 3 β-d-digitoxose

248 Cardenolide (C23)- digitalis-strophanthus type Digitalis lanata R 1 lanatoside A, R 1 =, R 2 =, R 3 =Ac, R 4 =Glc lanatoside B, R 1 =, R 2 =, R 3 =Ac, R 4 =Glc R 4 R Dig Dig Dig R 2 lanatoside C, R 1 =, R 2 =, R 3 =, R 4 =Glc digoxin, R 1 =, R 2 =, R 3 =, R 4 = deslanoside, R 1 =, R 2 =h, R 3 =, R 4 =Glc lanatoside A C =acetyl-purpureaglucoside A lanatoside B C =acetyl-purpureaglucoside B lanatoside C C =gluco-acetyl-digoxin

249 Cardenolide (C23)- digitalis-strophanthus type 스트로판치자 : Strophanthus kombe R 2 R 1 C 2 R 3 Rha- strophanthidin, R 1 =C, R 2 =, R 3 = K-strophanthin-β, R 1 =C, R 2 =, R 3 =Glc-Cym K-strophanthoside, R 1 =C, R 2 =, R 3 =Glc-Glc-Cym cymarin, R 1 =C, R 2 =, R 3 =Cym strophanthidol, R 1 =C 2, R 2 =, R 3 = cymarol, R 1 =C 2, R 2 =, R 3 =Cym emicymarin, R 1 =C 2,, R 3 =digitalose sarmentocymarin, R 1 =C 3, R 2 =, R 3 =sarmentose G-strophanthin (ouabain) C 3 C 3 C 3 C 3 D-sarmentose D-digitalose

250 Bufadienolide (C24)-(scilla-bufo-type) C17에 α-pyrone (coumalin) Bufo속의이하선및피지선분비물중에포합체로함유되고해총에도있음 섬수 : Bufo bufo gargorizans R R 2 R R 1 cinobufogenin, R=CC 3 resibufogenin, R= bufalin, R 1 =, R 2 =, R 3 = bufotalin, R 1 =, R 2 =, R 3 =Ac telocinobufagin, R 1 =, R 2 =, R 3 = gamabufotalin, R 1 =, R 2 =, R 3 =

251 해총 : Urginea scilla R C Glc R Glc R scillaren A, R= Rha-Glc 4 glucoscillaren A, R=Rha-Glc-Glc proscillaridin A, R=Rha 4 scilliglaucoside R= scillicyanoside R=Ac scilliroside R=Ac scillirubroside R=

252 3. Phytosterol β-sitosterol, campesterol, stigmasterol squalene으로부터 cycloartenol을거쳐생성 식물세포막구성에관여하고 cholesterol의흡수를길항하여체내의 cholesterol의농도를줄여준다. Ecdysteroid 곤충류가유충에서성충으로변태를하는데중요한역할을하는탈피 hormone 식물기원의화합물을 phytoecdysone이라고함 분포 : 꿀풀과, 미나리아재비과, 비름과, 백합과, 나한송과, 주목과, 고사리과등 우슬 : inokosterone, ecdysterone R 3 R 2 R 1 campesterol β-sitosterol stigmasterol inokosterone, R 1 =, R 2 =, R 3 = ecdysterone, R 1 =, R 2 =, R 3 = ponasteroside A, R 1 =Glc, R 2 =, R 3 =

253 Withanolide ergostane 기본핵중 22번과 26번탄소가산화되어 D-lactone이된화합물군을지칭 1번탄소도산화형 (ketone이나 α-)-1-oxo form이 90% 이상 13,14-seco 유도체도있음 특히 Solanaceae에서분리됨- Withania, Physalis, Acnistus, icandra, Lycium, Datura 속식물에서발견됨 Withania somnfera에서분리된 withanferin A, withanolide D, E는세포독성을나타냄 C 2 3 CC 3 CC withaferin A withacnistin R withanolide E, R= 4β-hydroxy withanolide, R=

254 steroidal alkaloid steroid 골격안또는 side chain에 을함유하는 pseudoalkaloid 백합과, 가지과 여로 : veratramine 절패모 : verticine,verticinone, peiminoside tomatidine R 절패모 verticine verticinone, R= peiminoside, R=Glc

255 3 C C 3 C 3 3 C C 3 solanidine green potato tubers C 3 C 3 rubijervine Veratrum album, European hellebore insecticide 3 C 3 C C 3 3 C C 3 conessine olarrhena spp used in India to treat amoebic dysentery C 3 (-)-solasodine

256 2. Tetraterpene (C40) -carotenoid GGPP 가축합되어생성되는 tetraterpene으로서탄화수소류 (carotene) 과그산화유도체 (xanthophyll) 의총칭 기본골격 : lycopene 구조적분류 - 탄화수소류 : β-carotene ( 당근 ), lycopene ( 토마토 ) - alcohol체 : zeaxanthin ( 옥수수 ) - 배당체 : crocin ( 사프란, 치자 ) - ketone 체 : capsanthin ( 고추 ) - 기타 : norcarotenoid 등 작용 : 천연색소, β-carotene (provitamin A) crocin, crocetin- 유효성분, 착색료 lycopene β-ring β carotene γ-ring γ carotene α-ring α carotene

257 β carotene α carotene zeaxanthin lutein

258 a b central cleavage generates two molecules of retinal β carotene central central 2 cleavage a 2 cleavage b excentric cleavage can generate one molecule of retinal retinal oxidative chain shorting retinol (Vitamin A1) dehydroretinol (Vitamin A2)

259 retinol (Vitamin A1) dehydroretinol (Vitamin A2) C C tretinoin (retinoic acid) isotretinoin (13-cis-retinoic acid) C 3 C acitretin retinol ADP + retinal hydrolytic cleavage of Schiff base opsin enzyme trans-cis isomerism of 11,12-double bond formation of Schiff base (imine) with amino group on protein hv absorption of light energy restores trans configuration of 11,12-double bone 2 -opsin 11-cis-retinal rodopsin opsin

260 ALKALIDS Reference) Alkaloids; ature s Cure or Blessing by M. esse Medicinal atural Products; A Biosynthetic Approach by P. M. Dewick

261 ALKALID 의정의 -1 Alkaoids are plant-derived substances that react like alkalis by W. Meissner (1819) itrogen-containing, nonacidic organic compounds by J.J.Berzelius (1837) itrogen-contaning organic bases by. Jacobsen (1882) All basic, organic compounds whether obtained either from animal or plant materials, or prepared artificially by I. Guareschi (1896) Compounds with nitrogen atoms bound in heterocyclic fashion,with greater or lesser degree of basic character, marked physiological effects, complicated molecular structure, which are found in plants, and with a few exceptions by E. Winterstein (1910)

262 ALKALID 의정의 -2 itrogen-containing bases of vegetable origin by A. Stoll (1953) itrogen-containing, basic compounds found in plants in general by P. Karrer (1959) A cyclic organic compound containing nitrogen in a negative oxidation state which is of limited distribution among living organisms by S. W. Pelletier (1983) Alkaloids are nitrogen-containing organic substances of natural origin with greater or lesser degree of basic character M. esser (2000)

263 ALKALID 의특성? aturally-occurring compounds that contain nitrogen Many have heterocyclic rings as a part of their structure They are found mostly in plants Many are physiologically active (often spectacularly) Many are used by native peoples for religious or medicinal purposes. Many are basic ( alkaline, due to an unshared pair on ) Those nitrogen compounds that are found in all organisms (i.e., amino acids, nucleic acids, etc.) are not considered alkaloids. Alkaloids are secondary metabolites, they are not involved in primary metabolism.

264 MRPIE 전형적인 ALKALID Plant source. Most alkaloids are found in plants. basic due to the unshared pair.. C 3 contains nitrogen heterocyclic ring Me This was the first alkaloid discovered (1804, Serturner). Found only in the pium Poppy - Papaver somniferum

265 Terminology 1) partly based on the systematic plant name (+ -ine) papaverine from Papaver species atropine from Atropa belladonna cocaine from Erythroxylum coca spegazzinine from Aspidosperma chakensis Spegazzini 2) Selected root word + suffixes (-ine, -idine, -aline, inine) Alkaloids from Vinca species; Vin - vincristine, vinblastine, vindoline primary, secondary, tertiary and quaternary amine itrile Amine oxide Imine itro,-disubstituted amide

266 W ARE ALKALIDS CLASSIFIED? Common classification schemes use either: The heterocyclic ring systems found as a part of the compound s structure The plant or plant family where they originate* Biosynthetic pathway * The majority of alkaloids (>90%) are found in plants - therefore, we will speak mostly about plants and their biochemistry.

267 ETERCYCLIC RIG SYSTEMS pyrrolidine pyrrole piperidine pyridine quinoline isoquinoline indole dihydroindole

268 ETERCYCLIC RIG SYSTEMS quinolizidine pyrrolizidine tropane C C benzylisoquinoline purine β-phenylethylamine

269 Some Examples of Classification BY RIG TYPE Me Me Me Me - P 3 C C 3 + C 3 emetine psilocybin 3 C C 3 C 3 C 3 nicotine caffeine

270 이미지를표시할수없습니다. 컴퓨터메모리가부족하여이미지를열수없거나이미지가손상되었습니다. 컴퓨터를다시시작한후파일을다시여십시오. 여전히빨간색 x가나타나면이미지를삭제한다음다시삽입해야합니다. Some Examples of Classification BY PLAT FAMILY : Amaryllis Alkaloids Me belladine Me Me lycorine The other three are biochemically derived from belladine. Me galanthamine C 3 tazettine These alkaloids are found in Amaryllidaceae Me daffodils narcissus lillies etc C 3 이미지를표시할수없습니다. 컴퓨터메모리가부족하여이미지를열수없거나이미지가손상되었습니다. 컴퓨터를다시시작한후파일을다시여십시오. 여전히빨간색 x가나타나면이미지를삭제한다음다시삽입해야합니다.

271 Some Examples of Classification BY PLAT F RIGI Cinchona Alkaloids Me quinine pium Alkaloids C 3 Me morphine

272 Some Examples of Classification 1. True alkaloids is part of a heterocyclic system complex molecular structures significant pharmacological activity restricted to the plant kingdom Amides Me Me Lactam Me - Exceptions to definitions - Me Me C C 3 2. Protoalkaloids itrogen is not present in a heterocyclic ring system but may exist outside the ring It is not always basic Biosynthesized from amino acid 3. Pseudoalkaloids ave a nitrogen in a heterocyclic ring ot biosynthesized from amino acid but rather from breakdown of nucleic acids -oxides R C 3 Zwitter ionics quarternary salts 3 C 3 C + - C 3 C C 3 + C 3 C 3 Cl C 3 - C - C - 3 C + 3 C C 2 3 C itro C 2 R

273 TE PURPSE F ALKALIDS I PLATS (?) The spectacular pharmacological properties of many of the alkaloids keeps asking about their purpose in plants. Many ideas have been advanced: Defense Mechanisms Insect Repellants erbivore Attractants itrogen Storage Growth Regulation Vestiges of ld Metabolic Experiments Metal ion transport (chelates) Insect Attractants Anti-fungals Competitive erbicides What seems most likely is that there are many reasons why plants elaborate alkaloids, and in many cases the purpose of the alkaloid may be unique to a given plant. References Manfred esse, Alkaloids -ature s Curse or Blessing, Wiley-VC, Weinheim, De (2002), Chapter 9, Biological Significance of Alkaloids, pages

274 Formation of Simple Imines remove R C R aldehyde or ketone R R C R + 2 primary amine R an imine Schiff base These reactions do not favor the formation of the imine unless: - the product (imine) is insoluble (crystallizes or precipitates) or - water is removed to drive the equilibrium - the reaction is enzyme-mediated

275 Mechanism of Imine Formation 2 R.... G 2 + C.. R acid-catalyzed addition 1 -- slow - G weak base addition - acid catalyzed R R C G C.. R R + proton exchanges -- + G R.... fast + C G + R loss of water (elimination) - R C R deprotonation an imine.. G R C R

276 ydrolysis of Simple Imines REVERSAL In an excess of aqueous acid, simple imines hydrolyze back to the aldehyde or ketone and the amine from which they were orginally formed.. R C R R C R R R an imine Imines that are not soluble, however, are difficult to hydrolyze.

277 MAIC REACTI one pot reaction - everything added at once R' C.. + R R + C C 3 C C 2 C R' R R aldehyde dialkylamine enolate component (has an acidic a-hydrogen) R' + C R R iminium ion like an aldol condensation second mole of R 2 takes C.. C 2 - The aromatic substitution step shown earlier cam also be regarded as a Mannich reaction..... C 3 +

278 FRMATI F ISQUILIE ALKALIDS C decarboxylation 1 2 hydroxylation Mannich reaction and aromatic substitution C C 3 C 3 methylation 6,7,8 Enz-B: C 3 C 3.. C 3 imine formation + Methylations could also have taken place before step three. C 3 C 3 C 3 Acetaldehyde C 3 C is a readily available metabolic intermediate

279 Shiff base formation: C- bond 형성 amine + aldehyde or ketone R 2 primary amine nucleophilic attack on to carbonyl C R equilibrium between protonated species; proton may be on or -, + R 2 elimination of water R Summary C imine or Schiff base R 1 R 2 secondary amine C R 1 R 2 R 1 R 2 C quaternary Shiff base Mannich reaction: amine + aldehyde or ketone + nucleophilic carbon R C imimium ion nucleophilic addition on to imminium ion C carbanion-type nucleophile R C C

280 The buliding block 2 2 L-rn C C 4 2 L-Lys 2 C C 5 C1: L-methionine C C2: acetyl-coa malonyl-coa C5: mevalonate C6C3: L-phenylalanine, L-tyrosine C6C2: L-phenylalanine, L-tyrosine 2 L-Phe C 2 L-Tyr C 6 C 2 Indole C2: L-tryptophan C4: L-ornitine C 2 C5: L-lysine L-Trp indole C 2

281 MST ALKALIDS ARE DERIVED FRM α-ami ACIDS SME F TE MAJR RELATISIPS ARE SW BELW C 2 2 C C ornithine 2 tryptophan R 2 2 lysine R 2 C R 2 and R R = phenylalanine R = tyrosine and R' R R =, C 3 R =, alkyl

282 The basic heterocyclic system in alkaloids pyrrole pyrrolidine piperidine pyrrolizidine quinolizidine tropane isoquinoline indole quinoline imidazole quinazoline

283 1. Alkaloids derived from ornithine 2 2 L-rn C C 4 pyrrolidine C C Plants 2 C -C 2 PLP 2 2 L-Glu 2 L-rn putrescine 2 SAM -methylation Shiff base formation deamine oxidase 2 C 3 C 3 C 3 -methyl- 1 -pyrroinium cation -methylputrescine (1) tropane alkaloids: atropine, scopolamine, cocaine, (2) pyrrolizidine alkaloids: Senecio genus, retronecine, senecionine (3) spermine, spermidine 3 C 3 C C 2 3 C C 2 RS atropine (-)hyoscine = scopolamine calysteigine A 3 CC 3 cocaine retronecine senecionine

284 Biosynthesis of cocaine and scopolamine 2 C SCoA 3 C SCoA 3 C C 3 3 C C 3 S methylation and stereospecific reduction of carbonyl to give 3β-alcohol 3 C S SCoA acetyl-coa SCoA C 3 -methyl- 1 -pyrroinium cation oxidation to generate pyrrolinium cation; formation of enolate anion in side chain CSCoA CSCoA CC 3 methylecgonine intramolecular Mannich reaction SAM ADP CoAS L-Phe 3 C ester formation C 3 R SCoA acetyl-coa C 3 hydrolysis 3 C intramolecular Mannich reaction; concomitant decarboxylation CC 3 cocaine 3 C -C 2 R tropinone SCoA C 3 C tropine stereospecific reduction of carbonyl to give 3α-alcohol L-Phe phenyl-lactic acid 3 C C 2 (-)-hyoscine (scopolamine)

285 1) tropane alkaloids pyrrolidine환과 piperidine환으로구성된화합물로 Solanaceae, Erythroxylaceae에만분포 Tropane환의 3번위치에 α- tropine-solanaceae β- tropine- Erythroxylaceae (1) Solanaceous alkaloids 스코폴리아근, 스코폴리아엽, 다투라엽, 벨라돈나근, 벨라돈나엽, 히요스엽 hyoscyamine, scopolamine, atropine 3 C C 2 RS 3 C C 2 3 C C 2 atropine (+) hyoscyamine (-)hyoscine = scopolamine

286 Biosynthesis of (-)-hyoscine C 2 L-Phe transamination C C CSCoA phenylpyruvic acid phenyl-lactic acid 3 C tropine 3 C C 2 rearrangement 3 C mutase + dehydrogenase (-)-hyoscyamine hyrorxylation by 2-oxo-glutarate-dependent dioxygenase 2 2-oxo-glutarare littorine Fe Enz 3 C C oxo-glutarare 3 C C 2 6β-hydroxyhyoscyamine oxidative formation of epoxide ring (-)-hyoscine (scopolamine)

287 C 2 L-Phe transamination C PMT: putrescine methyltransferase DA: diamine oxidase TR: tropinone reductase 6: hyoscyamine 6β-hydroxylase C ornitine putrescine PMT -methylputrescine phenylpyruvic acid phenyl-lactic acid 3 C tropine TR-I 3 C tropinone DA 4-amino-butanal 3 C C 2 spontaneous -methyl- 1-pyrrolinium ion (-)-hyoscyamine 6 3 C C C C 2 6β-hydroxyhyoscyamine (-)-hyoscine (scopolamine)

288 atropine 유래의의약품 3 C RS 3 C RS C 2 3 C homatropine tropicamide benzatropine(benztropine) RS cyclopentolate glycopyrronium

289 ATRPIE RICARD WILSTATTER ( ) Most of the work on the structure of atropine was done by:.. Professor Richard Willstatter Universities of Zurich, Berlin, Munich obel Prize 1930 w/ ans Fischer (eme and hemoglobin structures)

290 PLATS CTAIIG ATRPIE Solanaceae spp The following are plant sources of atropine and related alkaloids (scopolamine and cocaine are also related in structure). Atropa belladonna yoscyamus niger Datura strammonium Datura spp Mandragora officinarum Brugmansia sanguinea Scopolia spp Erythoxylon coca Deadly nightshade Black enbane Jimson weed, Thornapple Tree and Vine Daturas (S. Amer.) Mandrake Root Angel s Trumpet (Australia) Cocaine All have lengthly histories, dating to before the Greek and Roman Classical Era.

291 PARMACLGICAL PRPERTIES F ATRPIE Parasympathetic inhibitor antidote to cholinergic stimulants (nerve gases) Symptoms of poisoning dilated pupils (Caucasians) impaired vision mydriatic dryness of nose, mouth and skin (inhibits saliva and mucous secretions) extreme thirst analgesic properties hallucinations: sensation of distance rushing sound as in flying toxic dose very near efffective dose Component in hayfever/allergy drugs

292 Ethnobotany EARLY USES - WESTER CIVILIZATI Egypt (Ebers papyrus) 1500 B.C. described enbane omer (dyssey) described magic enbane drinks racle of Delphi smoked enbane seeds Medieval Witchcraft 1000 A.D. ointments and salves Witches sabbaths Mydriatic use by ladies ( bella donna ) in Middle ages in Italy Lycanthropy (animal changers) -WESTER USE Religious and medical use by Zuni and avajo indians (Datura) Indian and Chinese medicine Aztecs Toloache Shamanic/hallucinogenic use by South American natives (Jivaro)

293 Mandrake legends

294 2) Erythroxyaceous tropane alkaloids 코카엽에는 cocaine, cinnamoylcocaine, α-truxilline, β-truxilline, tropacocaine cocaine β- tropine 3 C CC 3 3 C CC 3 3 C cocaine cinnamoylcocaine tropacocaine 3 C CC 3 3 C CC 3 CC 3 C3 3 C 3 CC α-truxilline β-truxilline

295

296 Cocaine 유도체 2 2 n Bu 2 Et 2 Et 2 n Bu procaine benzocaine tetracaine/amethocaine oxybuprocaine Et 2 Pr 2 Et 2 RS n Bu RS proxymetacaine lidocaine/lignocaine bupivacaine prilocaine Pr ropivacaine Me RS mepivacaine RS articaine C 2 Me S Et 2 cinchocaine n Bu F 3 C 2 RS Et 2 2 RS RS CF 3 tovainide procamide mexiletine flecainide

297 2. Pyrrolizidine alkaloids hepatotoxic and carcinogenic mutagen, induce hepatic tumors oxidative deamination retronecine senecionine L-rn 2 or L-Arg AD AD 2 2 putescine putrescine homospermidine intramolecular Mannich reaction C C oxidative deamination 2 Shiff base formation C oxidative deamination X L-Ile C senecic acid retronecine senecic acid is derived from two molecules of Isoleucine senecionine

298 2. Alkaloid derived from lysine 2 C L-Lys 2 C 5 (1) piperidine alkaloids: lobeline, pelletierine (2) piperidine amides: Piperaceae, piperine (3) quinolizidine alkaloids: matrine, oximatrine, huperzine A (4) indolizidine alkaloids: castanospermine, swainsonine lobeline matrine castanospermine piperine

299 1) piperidine alkaloids lobeline: 로벨리아토, 호흠중추흥분, 천식기관지염에사용 (erbal drug) pelletierine: 석류피, 구충제 coniine: 코니움실 (hemlock, Conium maculatum L), 진경제, Lysine에서유래하지않음 C - C 2 PLP L-Lys cadaverine oxidative deamination via diamine oxidase hydrolysis decarboxylation 2 Schiff base formation 1 -piperidine Mannich reaction 2 x acetyl-coa CSCoA acetoacetyl-coa CSCoA pelletierine CSCoA 1 -piperidine cation biosynthesis of pelleterine

300 C 3 lobeline acetate C C octanoic acid (capric acid) L-Ala transamination pyruvic acid ADP Shiff base formation 2 (+)-coniine

301 2) piperidine amides: Piperaceae, piperine: Piper nigrum piperine Claisen reaction; chain extension using malonyl CoA reduction/dehydration reactions as in fatty acid biosynthesis SCoA malonyl-coa SCoA ADP SCoA - 2 SCoA piperine amide formation piperoyl-coa (piperic acid CoA ester) biosynthesis of piperine

302 3) quinolizidine alkaloids bicyclic nitrogen-containing heterocycles matrine, oxymatrine: 고삼 (Sophora flavescens), 스트레스성궤양예방 huperzine A: uperzia serrata (Thunb.) Trevis. = Lycopodium serratum Thunb. 가역적 acetylcholinesterase inhibitor, Blood-brain barrier 통과, glutamate에의한독성에대한보호작용, Alzheimer s disease 치료유망 (-)-lupinine: Lupinus 속 (Leguminosae)-독성물질 quinolizidine R matrine, R= sophoranol, R= R oxymatrine 2 huperzine A

303 Biosynthesis of (-)-lupinine 2 2 C 2 2 L-Lys - C 2 PLP 2 2 cadaverine deamine oxidase C 2 Shiff base formation aldol-type reaction between enamine and iminium hydrolysis of imine to aldehyde/amine (-)-lupinine C C Schiff base formation C C oxidative deamination C 2 further coupling (+)-lupinane (-)-sparteine cleavage of C 4 unit (+)-cytisine

304 4) indolizidine alkaloids swainsonine: Leguminosae, mannosidase inhibition castanospermine: glycosidase inhibitors, 항바이러스, anti-iv 효과 test 중 indolizidine swainsonine castanospermine 2 C 3 C 2 C 2 C acarbose acarbose : anti-diabetic drug 글루코바이정 : 장내효소의일종인 α-glucosidase에의한탄수화물의소화를억제, 장내포도당의흡수를지연

305 Cholinesterase inhibitors 2 C 3 C 3 3 tacrine Cognex (Park-Davis) donepezil Aricept (Eisai) rivastigmine Exelon (orvatis) 2 huperzine A (phase II) Lycopodium serratum 3 C 3 C C 3 galanthamine (genus arcissus, Amaryllidaceae) 3 C C 3 C 3 physostigmine (eserine) 3 C dehydroevodiamine

306 3. Alkaloid derived from nicotinic acid P 3-phosphoglyceraldehyde C 2 C L-Asp C C C C quinolinic acid C - C 2 nicotinic acid C C 2 C 2 C 3 C nicotinic acid (niacin/vitamin B 3 ) 3 nicotinamide C 3 trigonelline C 3 ricinine nicotinic acid (=Vitamin B 3, niacin) nicotine, anabasine: 연초, 농업용살충제 arecoline: 빈랑자, 구강청결제, 구충제 C 3 nicotine nornicotine anabasine ricinine: 피마자 CC 3 C CC 3 C C 3 C 3 arecoline arecaidine guvacoline guvacine

307 biosynthesis of nicotine C nicotinic acid 1,4-reduction of pyridine to dihydropyridine ADP dihydronicotinic acid - C 2 aldol-type reactionbetween enamine and iminium ion C 3 1,2-dihydropyridine -methylpyrrolinium cation L-rn putrescine 2 2 C 3 nicotine ADP + ADP + C 3

308 4. Alkaloid derived from Phenylalanine and Tyrosine (1) phenylethylamines mescaline, epinephrine, norepinephrine, (D-amphetamine, ephedrine, pseudoephedrine) (2) Isoquinoline Alkaliods 1.simple tetrahydroisoquinolines 2. benzylisoquinolines simple benzylisoquinolines reticuline, papaverine bisbenzylisoquinolines (+)-tubocurarine, (-)-curine aporphinoids apomorphine protoberberines and derivatives berberine, sanguinarine, palmatine, corydaline, dehydrocorydaline, chelidonine morphinane alkaloids morphine, codeine. thebaine 3. phenethylisoquinolines colchicine 4. alkaloids of the Amaryllidaceae lycorine, galanthamine 5. monoterpenoid isoquinolines emetine, cepheline (ipecacuanha alkaloids)

309 (1) phenylethylamines L-DPA dopamine mescaline C PLP SAM 2 2 (C 3 ) 2 L-Tyr tyramine hordenine 2 tetrahydrobiopterin C PLP 2 ascorbate SAM C 3 L-DPA dopamine noradrenaline (norepinephrine) adrenaline (epinephrine) SAM 3 C 2 3 C 2 SAM 3 C 2 SAM 3 C 3 C 2 C 3 C 3 mescaline

310 ephedrine, pseudoephedrine protoalkalids alkaloids derived by amination reaction ephedrine: Ephedraceae, noradrenaline 분비 α,β-교감신경훙분제, bronchial dilator pseudoephedrine: nasal decongestant synephrine: 오수유, 진피- adrenergic stimulant side-chain degradation via cinnamic acid nucleophilic attack on to ester with concomitane decarboxylation 2 C SCoA -C 2 L-Phe pyruvic acid transamination S R C 3 SAM 2 (-)-ephedrine (-)-norephedrine 2 S S SAM (-)-cathinone C 3 2 (+)-pseudoephedrine (+)-norpseudoephedrine

311 PEYLETYLAMIES Structural Element C C 2 The simplest Class of Alkaloids ot considered alkaloids by some - structures are too simple and only one or two biochemical steps away from mainstream metabolic compounds. All are derived from the amino acids phenylalanine or tyrosine: C 2 C C 2 phenylalanine C 2 C C 2 tyrosine FACT: most of the alkaloids come from amino acids

312 C 3 C C ephedrine Ephedrine C3 Sympathomimetic Amine compare found in ephedra spp Extract of ephedra was used in the early american west as a cure for asthma (Mormon Tea). Chinese medicine Ma uang for hay fever. Recently banned from organic weight-loss supplements! rganic appetite suppressant. C 3 C C 2 R C 2 C R R= orepinephrine R = C 3 Epinephrine (adrenalin) neurotransmitter / hormone R= amphetamine R = C 3 methamphetamine speed or crystal meth

313 PEYTE Lophophora williamsii Grows sparsely in the American Southwest, abundantly in arid high plains in Mexico. Indians have used it for centuries in religious ceremonies. Peyote was a serious item of trade amongst the native americans. It was used by tribes many hundreds of miles from its source. allucinogen vivid color hallucinations (vast film of fluctuating colors) nausea thirst The main alkaloid is mescaline Me Me Me Peyote buttons (cactus segments) were chewed by the indians C 2 C 2 2 mescaline

314 C 2 2 tyrosine Me 2 Me Me 2 mescaline Me Me Me Me Me 2 Me C 3 Me Me Me Me C 3 C 3 Me C 3 PSSIBLE BISYTETIC SEQUECES FR PEYTE ALKALIDS Me Me C 3 C 3 C 3

315 FRMATI F ISQUILIE ALKALIDS decarboxylation hydroxylation C Mannich reaction and aromatic substitution C C 3 C 3 methylation Enz-B: C 3.. C 3 imine formation + C 3 Methylations could also have taken place before step three. C 3 C 3 C 3 Acetaldehyde C 3 C is a readily available metabolic intermediate

316 TRASMISSI F TE SIGAL ALG A ERVE PAT ERVE AX MA synaptic vesicles (E inside) transmission of the signal is electrical SYAPSE a + K + transmission of the signal is chemical EURTRASMITTER (norepinephrine = E) neurotransmitter is released and removed by an enzyme after the binding; it is transported back to the synapse by CMT catechol -methyl transferase K + a + binding regenerates the electrical signal the binding opens a channel through which K + and a + ions flow generating an electrical signal

317 TPLGY F TE ERVUS SYSTEM EURTRASMITTERS AD RMES CS central nervous system SYMPATETIC ERVUS SYSTEM C C 2 C 3 (Adrenergic) nerve cell adrenal gland C C 2 oradrenalin Adrenalin blood stream RGA binding causes a response receptor sites

318 ITERCECTIS I TE BRAI C C 2 C 3 + C 3 C 2 C 2 C 3 C C3 norepinephrine (excitory) acetylcholine (inhibitory) C 2 C 2 2 serotonin (inhibitory) C C 2

319 MECAISMS F ACTI Amphetamines Ephedrine phenylethylamines minic E cause immediate release of E stimulate postsynaptic receptors (agonist) eventually deplete stores of E Cocaine blocks readsorption of E by the presynaptic terminus continues stimulation Mescaline stimulation similar to amphetamines not known why it stimulates color hallucinations and amphetamines do not

320 (2). Isoquinoline alkaloids 1. simple tetrahydroisoquinolines anhalonidine, anhalamine, corydaldine C 3 C R 3 C 3 C tetrahydroisoquinoline anhalonidine, R=C 3 anhalamine corydaldine

321 2. Benzyltetrahydroisoquinolines (1) simple benzyisoquinolines papaverine: 심근의평활근에억제적으로작용, 진경효과, 관상동맥확장작용 hygenamine (demethylcoclaurine): 평활근, 자궁근에대한이완작용 magnocurarine: 후박 (Magnolia officinalis, M. ovovata Thunb.) takatonine: 꿩의다리 (Thalictrum aquilegifoium, 미나리아재비과 ) (** 주의삼지구엽초 ( 음양곽 ) 6 7 3' 4' 5 8 2' 5' α 1' 6' 3 C 3 C 3 C 3 C 3 C 3 C 3 C C 3 C3 3 C + C 3 C 3 benzyltetrahydroisoquinoline papaverine takatonine higenamine magnocurarine

322 BISYTESIS F (+)-DEMETYLCCLAURIE tyrosine PLP (B6) 2 C PLP (B6) a benzylisoquinoline alkaloid 2 hydroxylase hydroxylase (SAM) R iminium ion + R Mannich (Arom Subst) 2 R = (+)-Demethylcoclaurine R=C 3 Papaverine R

323 L-Tyr -C 2 PLP PLP transamination tyramine 2 C 4-hydroxyphenylpyruvic acid - C 2 dopamine 2 C 4-hydroxyphenylacetaldehyde Mannich-like reaction (S)-norcoclaurine SAM 3 C (S)-coclaurine SAM 3 C methylation and dehydrogenations 3 C 3 C 3 C 3 C C 3 3 C 3 C papaverine reduction of planar iminium ion allows change in stereochemistry 3 C 3 C 3 C -nor-reticuline 3 C (S)--methylcoclaurine 2 ascorbate C 3 ADP C 3 ADP + C 3 SAM C 3 3 C (R)-reticuline 3 C 1,2-dehydroreticuliniium cation 3 C (S)-reticuline (S)-3-hydroxy- -methylcoclaurine Morphinans aporphines protoberberines benzophenanthridines

324 (2) bisbenzylisoquinolines 방기, 목방기, 칼룸바근, 규라레 Berberidaceae, Menispermaceae, Magnoliaceae tubocurarine: acetylcholine 길항, 근육이완, strychnine 중독의해소, shock 치료보조제, 근무력증 3 C one-electron oxidations of phenol groups give resonance-stabilized free radicals C 3 2 ADP 3 C C 3 radical coupling: this is likely to be a stepwise process 3 C 3 C (S)--methyl- coclaurine C 3 SAM C 3 3 C (S)--methyl- coclaurine C 3 2 ADP 3 C C 3 3 C C 3 ( 3 C) 2 C 3 tubocurarine

325 3 C 3 C 3 C C 3 C 3 C 3 ( 3 C) 2 3 C 3 C tubocurarine C 3 C 3 (-)-curine [(-)-(R,R)-bebeerine] C 3 (+)-(R,R)-isochondrodendrine

326 (3) aporphinoids apomorphine: morphine 에뜨거운 acid 를가하면생성, 파킨슨씨병에사용 -dopaminergic effect 오심, 구토 - 약물중독시사용대뇌에작용하여비아그라효과 (uprima) aristolochic acid: Aristolochia 속, 신장독성, 발암물질, phospholipade A 2 억제 oxidative coupling C 3 C 3 C a 7 6 C 3 C 3 C C 3 C 3 C aporphine (S)-reticuline (S)-isobolidine 3 C C C 3 3 C 3 C C C C 3 apomorphine glaucine aristolochic acid-a

327 Me Me C 3 Me C 3 Me Me Me Me [] (+)-corydine APRPIES standard benzylisoquinoline. C 3 coupling, rearomatization via enolization, SAM rotate 2 tyrosine Me Me. C 3 coupling, rearomatization via enolization, SAM ote how the benzene ring can rotate around its attachment to make a different substitution pattern. Me Me Me Me C3 (+)-glaucine

328 (4) protoberberines and derivatives berberine 을기본골격으로하는화합물 Papaveraveae, Berberidaceae, Ranuculaceae, Rutaceae, Menispermaceae 황련, 황백 : berberine, palmatine berberine: 고미, 고미건위정장제, tetrahydropalmatine: 진통작용, morphine 과같은내성은없음 corydaline, dehydrocorydaline ( 위액분비억제, 위궤양치료 )- 현호색 chelidonine: 백굴채 ( 애기똥풀 ), 평활근이완, 진경, 지사작용, 다량시 - 혈관운동중추억제, 혼수, 마비 noscarpine (=narcotine): 강력한중추성진해작용, 속효성, 의존성및금단증상없음 경련성기침에효과, 만성기침에유효 hydrastine: 히드라티스근, 혈관수축에의한지혈작용

329 protoberberine C 3 C 3 3 C hydrastine (phthalideisoquinoline-type) 3 C a c b protoberberine type C 3 b c a C 3 chelidonine (benzophenanthridine-type) C 3 protopine (protopine-type)

330 R 1 R 2 R 5 R 3 R 4 (+/-)-tetrahydroplamatine (-)-tetrahydrocoptisine (+)-corydaline (-)-tetrahydrocolumbamine (+)-corybulbine R 1 R 2 C 3 C 3 --C 2 ---C 2 -- C 3 C 3 C 3 C 3 R 3 C 3 --C 2 -- C 3 C 3 C 3 R 4 R 5 C 3 --C 2 -- C 3 C 3 C 3 C 3 C 3 R 1 + R 2 C 3 C 3 C 3 berberine, R 1 -R 2 =-C 2 - palmatine, R 1 =C 3, R 2 =C 3 jateorrhizine, R 1 =, R 2 =C 3 protopine

331 (5) morphinanes 아편 : morphine, codeine, thebaine ( 양귀비, Papaver somniferum) morphine: 중추신경억제제, 대뇌피질, 시상의통각중추및시냅스를마비하여진통효과연수의호흡중추억제하여호흡진정작용, 해수중추를억제하여진해작용위장 : 위산분비를억제하고, 장연동운동을저하시켜지사작용 codeine: 진해작용 thebaine R 3 C morphinane C 3 morphine, R= codeine, R=C 3 3 C thebaine C 3

332 3 C 3 C (R)-reticuline 3 C 3 C C 3 C 3 3 C 3 C 3 C 3 C demethylation of thebaine via hydroxylation. cleaving off methyl as formaldehydes thebaine one-electron oxidation of phenol groups to give resonance-stabilized free radicals C 3 C 3 2 ADP S2 nucleophilic attack with acetate as leaving group demethylation 3 C 3 C 3 C 3 C Ac C 3 radical coupling C 3 C3CSCoA esterification provides better leaving group 3 C C 3 3 C salutaridine ADP 3 C 3 C stereospecific reduction of carbonyl salutaridinol C 3 C 3 neophinone 3 C oripavine C 3 demethylation C 3 morphinone 3 C keto-enol tautomerism; allylic isomerization favored by conjugaton C 3 codeinone ADP stereospecific reduction of carbonyl 3 C codeine demethylation of codeine; probably via oxidation of methyl to hydroxymathyl and clevage of formaldehyde C 3 sterospecific reduction C 3 morphine

333 PIUM When the unripe seed capsule of the opium poppy (Papaver somniferum) is cut, a viscous milky liquid exudes. This is collected. n exposure to air the exudate dries and hardens, giving a hard but slightly sticky mass known as opium. Many alkaloids (> 40) are present in opium; the major one is morphine. MAJR PIUM ALKALIDS (% of total alkaloids) morphine 10-20% noscapine codeine % papaverine % thebaine % laudanosine< 0.1% 4-8% (also called narcotine)

334 PIUM PPPY Papaver somniferum

335 Collecting pium

336 ARDEED PIUM MASS PIUM, MRPIE AD ERI

337 MRPIE PARMACLGY Powerful analgesic and sedative - modifies the perception of pain rather than eliminates it mg of morphine take effect in 15 min - produces sleep and analgesia lasting 6 hr Unpleasant side effects - physiolgically addicting - constipating - respiratory depresssant overdoses cause death due to respiratory failure and severe anaphylaxis (shock) Lethal dose: 10 mg children, g for adults, addicts can tolerate up to 7 g per day

338 ERI Morphine is easily acetylated to diacetylmorphine using acetic anhydride. morphine C 3 C C C3 ERI diacetylmorphine riginally introduced by drug companies as the heroic new drug, with all properties of morphine except the addiction tendency.. this was soon proved to be false! eroin is more potent than morphine (it takes less for the same effect), lasts longer, and is more addicting. Addiction to heroin is a serious social problem today.

339 CDEIE Codeine can be produced by methylation of morphine morphine (C 3 ) 2 S 4 - CDEIE monomethylmorphine Codeine is a powerful antitussive - it blocks the cough reflex.

340 EKEPALIS From larger peptide structures found in the brain called endorphins. Bind to a pain-reducing receptor in the brain. C 3 2 C Leu-enkephalin Tyr-Gly-Gly-Phe-Leu SC 3 morphine The enkephalins are rapidly degraded in the body and are therefore not good for drug use. 2 C Met-enkephalin Tyr-Gly-Gly-Phe-Met

341 SYTETIC PIUM AALGESIC DRUGS C 3 C 3 3 C C 3 morphine dextromethorphan (levomethorphan) phenazocine Me naloxone C 3 oxycodone naltrexone (with cyclopropyl) 3 C C 3 pentazocine

342 SYTETIC PIUM AALGESIC DRUGS Et morphine C 3 C 3 Et meperidine (demerol) (pethidine) fentanyl Me 2 methadone

343 3. Phenethyl isoquinolines colchicine: 콜히쿰자, 급성통풍, 항염증, 진정효과, highly toxic L-Tyr L-Phe dopamine C 2 4-hydroxycinnamaldehyde 3 C Mannich-like reaction 3 C 3 C formation of cyclopropane ring via nucleophlic attack and loss of leaving group 3 C 3 C 3 C 3 C 3 C C 3 3 C 3 C 3 C 3 C (S)-autumnaline 3 C 3 C cleavage of cyclopropane generates aromatic 7-membered ring (tropolone) C 3 3 C 3 C 3 C 3 C C 3 C 3 SAM C 3 3 C 3 C 3 C 3 C hydrolysis of iminium ion and demethylation C 2 C 3 3 C 3 C 3 C 3 C 3 C oxidative coupling C 3 C 3 homomorphinane skeleton 2 C 3 acetyl-coa 3 C 3 C 3 C amide formation C 3 colchicine

344 4. alkaloids of the Amaryllidaceae L-Phe via cinnamic acids with side-chain cleavage C via Schiff base and reduction 2 galanthamine: acetylcholinesterase inhibitors Alzheimer s disease L-Tyr tyramine SAM 3 C norbelladine 4'--methynorbelladine 3 C A 3 C B 3 C C oxidative coupline lycorine 3 C C 3 galanthamine crinine SAM ADP 3 C -demethylgalanthamine 3 C 3 C nucleophilic attack of phenol on to dienone -demethylnarwedine

345 5. monoterpenoid isoquinoline alkaloids emetine: 아메바성이질, 오심유발, 약물중독시최토제로사용 cephaeline dopamine 3 CC 2 C Mannich-like reaction Glc 3 CC Glc -deacetylisopecoside 3 C 3 C 3 CC ipecoside C C 3 Glc formation of quaternary Schiff base (iminium ion) secologanin 3 CC 3 CC C reduction C= reduction C=C hydrolysis of ester decarboxylation enol-->keto - Glc 3 CC hydrolysis of glucoside liberates hemiacetal; further hydrolysis produces aldehyde and alcohol C C 2 dopamine 3 C 3 C repeat of Mannich-like reaction emetine R=C 3 cephaeline R= C 3 R

346 참고 Secoiridoid secologanin: 인동과식물등에존재, 모든 secoiridoid 의중간체 monoterpene indole alkaloid 의생합성에중요한전구체임 기본핵 iridoid secoiridoid C 3 CC Glc = C CC 3 Glc secologanin secologanin

347 참고 : biosynthesis of loganin and secologanin * PP * * GPP * * nerol * * C * C C C C * C C* *C 1/2 * Glc * C* * C*C 3 1/2 * Glc C CC 3 Glc loganin secologanin

348 5. Alkaloids derived from Tryptophan (1) simple indole aklaloids psilocybin, graminine (2) simple β-carboline alkaloids harmine, harmane, marmol (3) terpenoid indole alkaloids L-Trp C 2 indole C 2 yohimbine, reserpine, vinblastine, vincristine, strychnine, brucine, ellipticine (4) quinoline alkaloids quinine, quinidine, camptothecine (5) pyrroloindole alkaloids physostigmine (eserine) (6) ergot alkaloids lysergic acid, ergotamine, ergometrine

349 ATRAILIC ACID + C : 3 C 2 C C chorismic acid glutamic acid :B-Enz C 2 C 2 + C C C 2 anthranilic acid Tryptophan

350 anthranilic acid PLP indole C.. 2 PP C 2 C 2 serine reverse adol TRYPTPA C 2 P phosphoribosyl PP TRYPTPA C + P C 2 P - C 2-2 C C C + imine P tautomers enamine enol keto P tautomers P

351 (1) Simple indole aklaloids psilocybin, graminine C 2 - C 2 2 SAM C 3 SAM (C 3 ) 2 L-Trp trypyamine 5-hydroxy-L-Trp C 2 - C 2 (2) Simple β-carboline alkaloids harmine, harmane, marmol 2 Schiff base formation using aldehyde 2 5-hydroxytryptamine (5-T, serotonin) P psilocybin (C 3 ) 2 Mannich-like reaction; α-carbon can act as nucleophile pilocin (C 3 ) 2 trypyamine C R β-carboline R R R taumomerism to restore aromaticity R

352 PSILCYBI C SAM 2 tryptophan PLP 2 tryptamine [] Me 2 [] C 2 Me 2 PLP P ATP 2 5-hydroxytryptamine (5-T, serotonin) Me 2 psilocybin

353 (3) Terpenoid indole alkaloids strictosidine: 전구물질로이용 yohimbine, reserpine, vinblastine, vincristine, strychnine, brucine, ellipticine 등 tryptamine 2 C 3 CC Glc Mannich-like reaction 3 CC Glc secologanin strictosidine

354 There are a variety of alkaloids that have tryptophan and geraniol as their precursors. The geraniol precursor can yield a variety of skeletal pieces as it rearranges readily via a pathway containing two intermediates called loganin and secologanin. C Glu Glu MeC MeC geraniol loganin secologanin

355 SECLGAI Secologanin has so much functionality that it can open bonds, rotate and make new bonds, easily rearranging the carbon skeleton. Three principal skeleton types are shown below. These combine with tryptamine to form alkaloids (some examples are given). IRIDAE SKELT C Glu IRIDIDS MeC secologanin Corynanthe type CMe akuammicine CMe Aspidosperma type Iboga type CMe tabersonine catharanthine

356 Biogenetic homogeneity of indole alkaloids CC 3 akuammicine 3 CC ajamalicine C Glc Glc 3 CC 3 CC geraniol loganin secologanin corynanthe type tabersonine CC 3 aspidosperma type CC 3 catharanthine iboga type

357 C9 corynanthe 3 CC R 3 CC C 3 C 3 C 3 3 CC ajamalicine reserpine, R=C 3 deserpidine, R= serpentine 3 C 3 CC C 3 C 3 C 3 3 CC R R rescinnamine yohimbine strychnine, R= brucine, R=C3 3 C 3 C C 3 Ac ellipticine C 3 C 3 elliptinium acetate

358 Aspidosperma Ac CC 3 3 C CC 3 tabersonine vindoline C9 Iboga CC 3 catharanthine

359 vinca alkaloid: Catharanthus roseus G. Don. (=Vinca rosea L.) vinblastine, vincristine: tubule에결합하여 microtubule의생성저해, 항종양활성 acute leukemia, odgkin s disease, non-odgkin s lymphoma, breast cancer 등 Glc 3 CC strictosidine C 2 CC 3 preakuammicine stemmadenine C 2 CC 3 tabersonine CC 3 CC 3 CC 3 3 C Ac CC 3 vindoline catharanthine CC 3 Ac 3 C 2 C vinblastine, R=C 3 vincristine, R=C 3C R C 2 C 3

360 (4) Quinoline alkaloids 1) quinoline alkaloid: quinine, quinidine, cinchonidine, cinchonine 등 2) pyrroloquinoline: camptothecin * indole alkaloid 2 * quinoline alkaloid R R S R S R (-)-quinine R=C 3 (-)-cinchonidine R= (+)-quinidine R=C 3 (+)-cinchonine R= Et 2 3 C Et 2 Cl Cl Cl chloroquine hydroxychloroquine mepacrine CF 3 CF 3 mefloquine 3 C primaquine 2 F 3 C Cl Cl halofantrine

361 3 CC strictosidine Glc corynantheal C C R R S (-)-quinine R=C 3 (-)-cinchonidine R= ADP cinchoninone epimerization 2 C R S R ADP (+)-quinidine R=C 3 (+)-cinchonine R=

362 Bark of the Cinchona tree is stripped and powdered as a source of Quinine. Quinine is a febrifuge ( lowers body temperature, literally chases fever away ) and has been used for centuries to control the high-fever symptoms of malaria. Gin and Tonic gin and it Chinchona trees are found on the slopes of the Andes in Peru ( feet). Some years after the Spanish Conquest (about 1630), Jesuit missionaries learned about the tree it from the indian natives. Samples sent to Spain were reputed to have cured the spanish Countess of Chinchon, hence the name Cinchona. The indian name for the tree was quina, hence quinine. For many decades it was referred to as Jesuit powder or Peruvian bark.