佛波醇制备工艺优化及其衍生物的合成表征与细胞毒活性研究
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摘要
目前佛波醇制备过程比较繁琐,本研究首先对制备工艺进行优化,使制备周期缩短至3天。然后以佛波醇、二十碳五烯酸、二十二碳六烯酸、花生酸为原料,设计合成了18个新化合物,运用~1H NMR,~(13)C NMR,HR-MS对化合物进行结构表征,并测试了这些化合物对人正常胚肺成纤维细胞(MRC-5)的毒性。结果显示13个化合物对正常细胞毒性较大(IC_(50)<38.12μmol/L),5个化合物毒性较小(IC_(50)> 100μmol/L)。佛波醇的12位羟基、13位羟基分别与长链饱和脂肪酸形成单酯时毒性较低,实验结果为佛波醇的结构修饰提供参考。
The process of phorbol preparation is complicated,in this study,the preparation process was optimized and the preparation cycle was shorten to 3 days.18 new compounds were designed and synthesized using phorbol,eicosapentaenoic acid,docosahexaenoic acid and arachidic acid.The compounds were characterized by ~1H NMR,~( 13)C NMR and HR-MS,and the toxicity of these compounds to hunan cells(MRC-5) was tested.There were 13 compounds with high cytotoxicity(IC_(50) < 38.12 μmol/L) and 5 compounds with low cytotoxicity(IC_(50) > 100 μmol/L) in the cytotoxicity asssy.The phorbol-12-monoester and phorbol-13-monoester,which were esterified with long-chain saturated fatty acids had low cytotoxicity.The results of the test could provide guidance for phorbol structural modification.
The process of phorbol preparation is complicated,in this study,the preparation process was optimized and the preparation cycle was shorten to 3 days.18 new compounds were designed and synthesized using phorbol,eicosapentaenoic acid,docosahexaenoic acid and arachidic acid.The compounds were characterized by ~1H NMR,~( 13)C NMR and HR-MS,and the toxicity of these compounds to hunan cells(MRC-5) was tested.There were 13 compounds with high cytotoxicity(IC_(50) < 38.12 μmol/L) and 5 compounds with low cytotoxicity(IC_(50) > 100 μmol/L) in the cytotoxicity asssy.The phorbol-12-monoester and phorbol-13-monoester,which were esterified with long-chain saturated fatty acids had low cytotoxicity.The results of the test could provide guidance for phorbol structural modification.
引文
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7 Guo H(郭虎).Research on extraction and separation of phorbol alcohol[D].Chongqing:Chongqing Medical University(重庆医科大学),2011
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9 Boudreault PL,Mattler JK,Wender PA.Studies on the regio-and diastereo-selective epoxidation of daphnanes and tiglianes[J].Tetrahedron Lett,2015,56:3423-3427.
10 El-Mekkawy S,Meselhy MR,Abdel-Hafez AA,et al.Inhibition of cytopathic effect of human immunodeficiency virus type-1 by various phorbol derivatives[J].Chem Inform,2002,33:523-529.
11 Wender PA.Mapping phorbol ester binding domains of protein kinase C(PKC):The design,synthesis and biological activity of novel phorbol ester dimers[J].Synth,1999,1999(S1):1401-1406.
12 Tseng SS,Van Duuren BL,Solomon JJ.Synthesis of 4-aalpha-phorbol 9-myristate 9a-acetate and related esters[J].J Org Chem,1977,42:3645.
2 Wang JF,Yang SH,Liu YQ,et al.Five new phorbol esters with cytotoxic and selective anti-inflammatory activities from Croton tiglium[J].Bioorg Med Chem Lett,2015,25:1986-1989.
3 Beans EJ,Fournogerakis D,Gauntlett C,et al.Highly potent,synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo[J].PNAS,2013,110:11698-11703.
4 Asada Y,Sukemori A,Watanabe T,et al.Isolation,structure determination,and anti-HIV evaluation of tigliane-type diterpenes and biflavonoid from Stellera chamaejasme[J].J Nat Prod,2013,76:852-857.
5 Wang XL(王新丽).Antitumor effects of phorbol ester combined with TPA chemotherapy[D].Zhengzhou:Zhengzhou University(郑州大学),2014.
6 Lewin SR,Rouzioux C.HIV cure and eradication:how will we get from the laboratory to effective clinical trials?[J].Aids,2011,25:885-897.
7 Guo H(郭虎).Research on extraction and separation of phorbol alcohol[D].Chongqing:Chongqing Medical University(重庆医科大学),2011
8 Cairnes DA,Mirvish SS,Wallcave L,et al.A rapid method for isolating phorbol from croton oil[J].Cancer Lett,1981,14(1):85-91.
9 Boudreault PL,Mattler JK,Wender PA.Studies on the regio-and diastereo-selective epoxidation of daphnanes and tiglianes[J].Tetrahedron Lett,2015,56:3423-3427.
10 El-Mekkawy S,Meselhy MR,Abdel-Hafez AA,et al.Inhibition of cytopathic effect of human immunodeficiency virus type-1 by various phorbol derivatives[J].Chem Inform,2002,33:523-529.
11 Wender PA.Mapping phorbol ester binding domains of protein kinase C(PKC):The design,synthesis and biological activity of novel phorbol ester dimers[J].Synth,1999,1999(S1):1401-1406.
12 Tseng SS,Van Duuren BL,Solomon JJ.Synthesis of 4-aalpha-phorbol 9-myristate 9a-acetate and related esters[J].J Org Chem,1977,42:3645.
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