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1 ISSN (PRINT) ISSN (ONLINE) 약학회지제 61 권제 4 호 222~226 (2017) Yakhak Hoeji Vol. 61, No. 4 DOI /psk 종설 Short Report 다이셀레닐네이션을이용한알킬설포닐기가치환된새로운다이피리다지닐다이셀레나이드의형성반응 김채원 박명숙 # 덕성여자대학교약학대학 (Received July 26, 2017; Revised August 22, 2017; Accepted August 26, 2017) Formation of Novel Alkylsulfonyl Group Substituted Dipyridazinyl Diselenides by Diselenylation Chaewon Kim and Myung-Sook Park # College of Pharmacy, Duksung Women s University, Seoul 01369, Korea Abstract A new series of bis (pyridazinyl) diselenides was synthesized by diselenylation from pyridazinyl chloride for search of antiproliferative agents. The process involves the alkylthiolation, oxidation (sulfonylation and sulfinylation) and diselenylation from 3,6-dichloropyridazine. The alkylsulfonyl (or sulfinyl) pyridazinyl chloride (3c, 4a~4f) could be converted to target diorganodiselenides 5c, and 6a~6f with selenium, hydrazine hydrate under atmospheric pressure in the presence of sodium hydroxide. The structures of the synthetic compounds were characterized using 1 H and 13 C NMR spectroscopy. Keywords Diaryl diselenides, Organoseleniums, Bis(alkylsulfonylpyridazinyl) diselenides, Diorganodiselenides, Diselenylation Selenium은우리몸에서건강에중요한역할을담당하고있는필수미량원소이다. Selenium은주로 selenocysteine과같은형태로우리몸에삽입되어세포의생리작용을담당하고있다. 1) 그동안여러가지 organoselenium 유도체들의생리작용이보고되었고, 2) 이중특히 diselenide 유도체들이현저한항암작용을나타내는것으로주목을받았다. 3) Diselenide 유도체중 bis(4- aminophenyl)diselenide 유도체가 leukemia cell lines에서매우좋은증식억제효과를나타내었다. 2) 또한 diphenyl diselenide 유도체와그치환체들이여러가지암세포들에서세포독성효과를나타내었다. 4) 최근, seleno-l-cysteine와같은 diselenide의구조를응용하여 selenylsufide 유도체 (R-Se-S-R) 를합성하고수용성 # Corresponding Author Myung-Sook Park College of Pharmacy, Duksung Women s University, Seoul 01369, Korea Tel.: Fax.: mspark@duksung.ac.kr nanosized-glutathione peroxidase 유사체의개발을타진한연구도보고되었다. 5) Organoselenium 유도체는일반적으로 selenium의불안정한성질로인해제조하기가쉽지않다. 여러연구자들에의해다양한합성법이보고되어왔지만, 아주간단하고효율적인방법은보고되지않았다. K. K. Bashin은헤테로고리를가진 diselenide 유도체를창출하기위하여 dipyridyl diselenide 유도체를합성하여그합성법을보고하였다. 6) 본연구실에서는이를응용하여헤테로고리를 pyridazine 고리로대체한 dipyridazinyl diselenide 화합물들의합성과잠재적항암효과를보고한바있다. 7) 즉, Diphenyl diselenide 구조의 phenyl기대신 pyridazine으로대체시킨방향족헤테로고리로되어있는 diselenide 유도체이다. 최근, 본연구실에서는 dipyridazinyl diselenide 유도체인 alkoxy기또는 alkylthio기가치환된 dipyridazinyl diselenide 유도체를합성하여보고하였다. 7) 그러나 alkylsulfonyl기가치환된 dipyridazinyl diselenide는지금까지보고되지않았다. 본연구에서는 diphenyl diselenide 구조와같은 diaryl diselenide 222

2 Formation of Novel Dipyridazinyl Diselenides 223 Fig. 1 Reported dipyridazinyl diselenides and target 1,2-bis(alkylsulfonylpyridazinyl) diselenides. 의구조를바탕으로하여여러가지 alkylsulfonylpyridazinyl diselenide 유도체를설계하였다. Fig. 1에서보는바와같이 pyridazine ring 의 para 위치에 alkoxy 기나 alkylthio기대신에 alkylsulfonyl기로치환된구조들을합성하여보고하고자한다. 실험방법 (Experimental Methods) 시약및분석기기시약은 Sigma-Aldrich, TCI 등에서구입했고, 융점측정은 Büchi 545 Melting Point apparatus를사용하였다. 1 H NMR 및 13 C NMR spectroscopy는 Bruker 사의 300 MHz NMR spectrometer 를사용하여측정했다. 이때모든화학이동들은 TMS를 reference 로했으며 ppm단위로기록했다. 반응의진행은 silica gel 60F 254로피막된 TLC plate를이용하여 n-hexanes: ethyl acetate (3/1, 2/1, 1/1 등 ) 으로전개하고, spot은 UV light로확인했다. General synthetic procedure for 3-alkylthio-6-chloropyridazine (2a~2f) 화합물 2a~2f은 3,6-dichloropyridazine 1 으로부터 methane thioxide, ethane thiol, propane thiol, butane thiol, pentane thiol, hexane thiol을시약으로이용하여 alkylthiolation 반응으로합성되었다. 이 pyridazine 고리의친핵성치환반응은일반적인 thiolation 반응의방법을응용하였다. 화합물 2a~2f 은 NMR data로분석하여확인하였다. General synthetic procedure for 3-alkylsulfonyl(or sulfinyl)- 6-chloropyridazine (3c, 4a~4f) 화합물 3c, 4a~4f은 3-alkylthio-6-chloropyridazine 2a~2f 으로부터 hydrogen peroxide를이용한산화반응으로합성되었다. 이반응은앞서보고한산화반응의방법을변형하였으며, 화합물 3c를위한산화제로는 m-cpba가사용되었고, 화합물 3c와 4a~4f의 NMR 분석 data는문헌의보고와일치하였다. 9) General synthetic procedure for the 1,2-bis( alkylsulfinylpyridazinyl) diselenides (5c), and the 1,2-bis (alkylsulfonylpyridazinyl) diselenides (6a~6f) Dimethylformamide (DMF) (25 ml) 에 sodium hydroxide (0.36 g, 9 mmol) 와 selenium (0.47 g, 6 mmol) 을가하여잘저어혼합용액을만들었다. 이용액에 98% hydrazine hydrate (0.19 ml, 4mmol) 를소량씩서서히가했다. 이반응혼합액을 40 o C에서약 2 시간동안교반하여 Na 2 Se 2 를생성시켰다. 이반응혼합액에 alkylsulfonylpyridazinyl chloride 4a~4f (or 3c) (6 mmol) 를서서히가하고, 반응액을실온에서 2~4시간동안교반하면서반응시켰다. 반응을종료하고 30분정도방치하여미반응의 selenium 을침강시켰다. 상등액을감압여과하여잔류하는 selenium을제거하고충분한물로세척한후, 여액을취해과량의얼음을가하고실온에서약 3~4일간방치하여반짝이는갈색의결정을얻었다. 1,2-Bis(propylsulfinylpyridazinyl) diselenide (5c): Reaction time: 22 h; Yield: 32%; mp o C; 1 H NMR (CDCl 3 ) δ 8.21 (d, J=8.8 Hz, 2H, pyridazine), 8.07 (d, J=9.0 Hz, 2H, pyridazine), 3.18 (t, J=7.8 Hz, 2H, propyl), (m, 2H, propyl), 1.07 (t, J=7.4 Hz, 3H, propyl); 13 C NMR (CDCl 3 ) δ , , , (pyridazine), 57.27, 15.53, (propyl). 1,2-Bis(methylsulfonylpyridazinyl) diselenide (6a):Reaction time: 4 h; Yield: 42%; mp 231~235 o C; 1 H NMR (CDCl 3 ) δ 8.24 (d, J=8.8 Hz, 2H, pyridazine), 8.13 (d, J=8.8 Hz, 2H, pyridazine), 3.46 (s, 3H, methyl); 13 C NMR (CDCl 3 ) δ , , , Vol. 61, No. 4, 2017

3 224 김채원 박명숙 (pyridazine), (methyl). 1,2-Bis(ethylsulfonylpyridazinyl) diselenide (6b):Reaction time: 4 h; Yield: 46%; mp 212~215 o C; 1 H NMR (CDCl 3 ) δ 8.22 (d, J=8.8 Hz, 2H, pyridazine), 8.06 (d, J=8.8 Hz, 2H, pyridazine), (q, J=7.4 Hz, 2H, ethyl), 1.41 (t, J=7.4 Hz, 3H, ethyl); 13 C NMR (CDCl 3 ) δ , , , (pyridazine), 47.08, (ethyl). 1,2-Bis(propylsulfonylpyridazinyl) diselenide (6c):Reaction time: 2 h; Yield: 38%; mp 202~206 o C; 1 H NMR (CDCl 3 ) δ 8.19 (d, J=8.8 Hz, 2H, pyridazine), 8.03 (d, J=8.8 Hz, 2H, pyridazine), 3.56 (t, J=7.8 Hz, 2H, propyl), (m, 2H, propyl), 1.07 (t, J=7.4 Hz, 3H, propyl); 13 C NMR (CDCl 3 ) δ , , , (pyridazine), 54.13, 15.96, (propyl). 1,2-Bis(butylsulfonylpyridazinyl) diselenide (6d):Reaction time: 2 h; Yield: 22%; mp 195~203 o C; 1 H NMR (CDCl 3 ) δ 8.19 (d, J=8.8 Hz, 2H, pyridazine), 8.03 (d, J=8.8 Hz, 2H, pyridazine), 3.57 (t, J=8.0 Hz, 2H, butyl), (m, 2H, butyl), (m, 2H, butyl), 0.93 (t, J=7.2 Hz, 3H, butyl); 13 C NMR (CDCl 3 ) δ , , , (pyridazine), 53.55, 29.72, 25.75, (butyl). 1,2-Bis(pentylsulfonylpyridazinyl) diselenide (6e):Reaction time: 4 h; Yield: 32%; mp 224~228 o C; 1 H NMR (CDCl 3 ) δ 8.21 (d, J=8.8 Hz, 2H, pyridazine), 8.06 (d, J=8.8 Hz, 2H, pyridazine), 3.59 (t, J=8.0 Hz, 2H, pentyl), (m, 2H, pentyl), (m, 2H 2, pentyl), 0.90 (t, J=7.0 Hz, 3H, pentyl); 13 C NMR (CDCl 3 ) δ , , , (pyridazine), 52.45, 30.39, 29.71, 22.08, (pentyl). 1,2-Bis(hexylsulfonylpyridazinyl) diselenide (6f): Reaction time: 4 h; Yield: 15%; mp 217~221 o C; 1 H NMR (CDCl 3 ) δ 8.22 (d, J=8.8 Hz, 2H, pyridazine), 8.05 (d, J=8.8 Hz, 2H, pyridazine), 3.62 (t, J=7.7 Hz, 2H, hexyl), (m, 2H 2, hexyl), (m, 2H 2, hexyl), 0.87 (t, J=7.0 Hz, 3H, hexyl); 13 C NMR (CDCl 3 ) δ , , , (pyridazine), 52.49, 31.09, 27.99, 22.27, 21.98, (hexyl). 실험결과및고찰 (Results and Discussion) 본연구에서는유용한유기셀레늄화합물로주목을끌고있는 diphenyl diselenide의구조를바탕으로새로운헤테로고리형태의 diselenide 유도체구조를설계하였다. 유기셀레늄화합물들 Scheme 1 Synthesis of target 1,2-bisalkylsulfonyl (or sulfinyl) pyridazinyl diselenides (5c, and 6a~6f). J. Pharm. Soc. Korea

4 Formation of Novel Dipyridazinyl Diselenides 225 을제조하기위해 K. K. Bhasin의 bis(2-pyridyl) diselenide 유도체합성법을참고하였다. 6) 본연구에서는 dialkylsulfonylpyridazinyl diselenide 유도체를제조하기위해서앞서보고한 dialkoxypyridazinyl diselenide 유도체와 dialkylthiopyridazinyl diselenide 유도체의제조 7, 8) 법을응용하게되었다. 신규유용한 diselenide 유도체를도출하기위해상업적으로이용가능한 3,6-dichloropyridazine을출발물질로삼았다. 전체합성의과정은 Scheme 1에서보는바와같이 alkylthiolation을통해 pyridazine핵의 para-위치에다양한 alkylthio기를도입하였고, oxidation 을거쳐서 sulfonyl( 또는 sulfinyl) 기로전환하였으며, diselenylation의반응들을진행하여최종 diselenide 화합물을목표화합물로생성하였다. 산화반응을위해서산화제 H 2 O 2 와 m- CPBA 사용하여실온에서 18~72시간교반하여반응하였고, 반응중간체 3c, 4a~4f를성공적으로제조하였으며, sulfone 화합물의분석 data는문헌과일치하였다. 10) Diselenylation을위해서 Lee 등의합성방법을 8, 11) 응용하였으며, 핵심시약으로 disodium diselenide를용시조제하여반응에이용하였다. Disodium diselenide를만들기위해서는 DMF에분말상태의 selenium과 NaOH를가한용액에 hydrazine hydrate 를소량씩천천히가했다. 처음반응액의색깔은흑색을띠나점차반응이진행되어 disodium diselenide로전환될수록흑녹색으로변했다. 이반응액에 alkylsulfonylpyridazinyl chloride 3c, 4a~4f를서서히실온에서가하여 2~4시간동안반응하고, diselenide 5c, 6a~6f를생성시켰다. 이반응에서는 monoselenides 와 diselenides 가함께생성될수있으므로반응온도를실온이상으로높이지않으며반응하였다. 환류반응에서는 monoselenides 가동시에생성되었다는선행연구를 8) 참고로하였다. Proton-NMR 에서는 diselenylation 된 6a~6f의경우 selenylation 이전의 pyridazine 고리의수소 Ha(7.79~7.81 ppm) 가반응이후에는 8.03~8.13 ppm으로변화되었음을확인할수있었다. 목표화합물 dialkylsulfonylpyridazinyl diselenides 6a~6f의 1 H NMR spectrum을 diselenylation 반응의출발물질인 alkylsulfonylpyridazinyl chloride의 1 H NMR spectrum과비교하였다. Pyridazine 고리에서 selenium이도입된바로옆탄소의수소 Ha와그옆의 coupling하는이웃수소 Hb의동태를관찰하였고, Fig. 2에서보는바와같이수소 Ha가더많이 down shift 함을알수있었다. 반응출발물질 4a~4f의구조와비교해볼때 Ha에영향을주는이웃은원소 chlorine으로이는전자를끌어당기는전자적성질을가지고있고, 반면에반응생성물의구조에서는원소 selenide 로전자를공여해주는전자적성질을가지고있어서수소 Hb에비해수소 Ha가더 down field 방향으로더화학적인이동을한것으로보인다. 이와같은현상은본연구실에서앞서보고한 dialkoxypyridazinyl diselenide 화합물에서도비슷하게나타났다. 전체적으로 diselenide 유도체 6a~6f의융점이출발물질 pyridazinyl chloride 4a~4f의융점과크게다르다. 한예로 ethylsulfonylpyridazinyl chloride 4b는 68~70 o C에서녹았으나 diselenylation의생성물인 diethylsulfonylpyridazinyl diselenide 유도체 6b는 212~215 o C에서녹아융점이크게상승하였다. 이러한융점의변화는 Table I에서보는바와같이다른 alkyl기를가진유도체에서도같은현상으로나타났다. Diselenide 유도체 6a~6f의제조를위한반응수득율은 15~46% 였다. Table I에서보는바와같이 alkylsulfonyl기의길이가길어짐에따라전반적으로반응수득율이낮아지는경향을보였다. 반응수득율이낮아진다는것은반응의진행이더어려 Fig. 2 Changes of 1 H NMR chemical sfift after diselenylation. Vol. 61, No. 4, 2017

5 226 김채원 박명숙 Table I Optimal conditions and production yields for final bis(alkylsulfonyl(or sulfinyl)pyridazinyl) diselenides (5c, 6a~6f) a No. R X mp o C Rxn time (h) Yield(%) 5c a n-propyl SO a methyl SO b ethyl SO c n-propyl SO d n-butyl SO e n-pentyl SO f n-hexyl SO The reagent for oxidation is the m-cpba. 웠다는것인데, 이는두가지로생각해볼수있다. 하나는 alkyl 기가길어지면서용해도차이가생겨서 diselenide dianion의친핵적인공격에차이를보였다는것이고, 다른하나는새로생성되는 diselenide기가 alkyl기에비해상대적으로부피가작기때문에 steric hindrance에의한반응충돌계수가낮아졌다는것이다. 결론 (Conclusion) 본연구에서는새로운항암성약물을개발하기위하여 alkylsulfonyl기를가지고있는 dipyridazinyl diselenide 화합물을설계하고합성하였다. 목표화합물의합성을위해 pyridazine 유도체의 diselenylation 반응에대해고찰하였다. 최종목표화합물은 pyridazine 의 para 위치에다양한 alkylsulfonyl( 또는 sulfinyl) 기를도입한 bis(alkylsulfonylpyridazinyl) diselenide 유도체였다. 목표화합물을위한합성경로는 alkylthiolation과연이은 oxidation 반응, 그리고 diselenylation 반응으로진행하였고, 7종의신규 diselenide 화합물 (5c, 6a~6f) 을생성하였다. 감사의말씀 (Acknowledgment) 본연구는덕성여자대학교 2016년도교내연구비에의하여지원되었으며, 이에감사드립니다. References 1) Fernandes, A. P. and Gandin, V. : Selenium compounds as therapeutic agents in cancer. Biochim. Biophys. Acta. 1850, 1642 (2015). 2) Plano, D., Baquedano, Y., Ibáñez, E., Jiménez, I., Palop, J. A., Spallholz, J. E. and Sanmartín, C. : Antioxidant-prooxidant properties of a new organoselenium compound library, Molecules 15, 7292 (2010). 3) Paula, M. T., Franco, J. L., Leal, R. B. and Rocha, J. B. T. : Diphenyl diselenide induces apoptotic cell death and modulates ERK1/2 phosphorylation in human neuroblastoma SH-SY5Y cells. Arch. Toxicol. 85, 645 (2011). 4) Nedel, F., Campos, V. F., Alves, D., McBride, A. J. A., Dellagostin, O. A., Collares, T., Savegnago, L. and Seixas, F. : Substituted diaryl diselenides: cytotoxic and apoptotic effect in human colon adenocarcinoma cells. Life Sci. 91, 345 (2012). 5) Haratake, M., Tachibana, Y., Emaya, Y., Yoshida, S., Fuchigami, T. and Nakayama, M. : Synthesis of nanovesicular glutathione peroxidase mimics with a seleneylsulfide-bearing lipid. ACS Omega 1, 58 (2016). 6) (1) Bhasin, K. K. and Singh, J. : A novel and convenient synthesis towards 2-pyridylselenium compounds: X-ray crystal structure of 4,4'-dimethyl-2,2'-dipyridyl diselenide and tris(2-pyridylseleno)methane. J. Organometal. Chem. 658, 71 (2002). (2) Bhasin, K. K., Bhandal, B. S., Singh, J., Singh, N., Singh, K. N. and Singh, P. : A new and convenient route to 2,2'- dipyridyl diselenide/ditelluride and some of their alkyl/aryl derivatives through BF 3 -complexed pyridyl carbanion. Synth. Commun. 32, 1319 (2002). (3) Bhasin, K. K., Singh, N., Kumar, R., Deepali, D. G., Mehta, S. K., Klapoetke, T. M. and Crawford, M. J. : A convenient synthesis of some symmetrical and unsymmetrical diarylmethyl sulfur and selenium compounds: X-ray crystal structure of diphenylmethylseleno- 2-propene and bis[p-chlorophenyl (phenyl)methyl] diselenide. J. Organometal. Chem. 689, 3327 (2004). 7) Kim, C., Lee, J. and Park, M. S. : Synthesis of new diorganodiselenides from organic halides: their antiproliferative effects against human breast cancer MCF-7 Cells, Arch. Pharm. Res. 38, 659 (2015). 8) Lee, S. H., Kim, S. B. and Park, M. S. : One-pot synthetic method of symmetrical diaryl diselenides using Na 2 Se 2, J. Kor. Chem. Soc. 55, 546 (2011). 9) Park, E. H. and Park, M. S. : Oxidation of pyridazinyl sulfides; synthesis of new pyridazinyl sulfoxides and pyridazinyl sulfones with aqueous hydrogen peroxide. Yakhak Hoeji 56, 390 (2012). 10) Kim, C. and Park, M. S. : Synthesis and antiproliferative activities of chloropyridazine derivatives retain alkylsulfonyl moiety. Bull. Korean Chem. Soc. 37, 1858 (2016). 11) Lee, J., Kim, C. and Park, M. S. : Selenium-containing bis (alkylselanyl)pyridazines: synthesis and evaluation of antiproliferative activities, Bull. Korean Chem. Soc. 37, 234 (2016). J. Pharm. Soc. Korea

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