胆酸酰氧基膦酸酯衍生物的合成及抗肿瘤活性
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摘要
以胆酸和亚磷酸酯为原料,在缩合剂二环己基碳二亚胺(DCC)和4-二甲基吡啶(DMAP)的催化下进行酯化反应,合成了10个未见报道的胆酸酰氧基膦酸酯衍生物,所有目标化合物均经过TG,IR,1 H NMR,31P NMR和HRMS对其进行了结构确认.利用MTT法测定了目标化合物的抗肿瘤活性,结果显示:目标化合物4H,4I,4J对人肝癌细胞(HepG2)表现出较好的增殖抑制作用.
10cholic acid-phosphonate derivatives based on cholic acid andα-hydroxyphosphonate have been synthesized by using DCC/DMAP condition.These compounds were reported for the first time and confirmed by TG,IR,1 H NMR,31 P NMR and HRMS.And the antitumor activity of the cholic acid derivatives have been measured by MTT assay method.The results showed that the target compounds exhibited certain antitumor activity against HepG2,especially 4H,4I,4J.
10cholic acid-phosphonate derivatives based on cholic acid andα-hydroxyphosphonate have been synthesized by using DCC/DMAP condition.These compounds were reported for the first time and confirmed by TG,IR,1 H NMR,31 P NMR and HRMS.And the antitumor activity of the cholic acid derivatives have been measured by MTT assay method.The results showed that the target compounds exhibited certain antitumor activity against HepG2,especially 4H,4I,4J.
引文
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[3]LAKE A D,NOVAK P,SHIPKOVA P,et al.Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease[J].Toxicol Appl Pharmacol,2013,268(2):132-140.
[4]WU D,JI S,YAN W,et al.Design,synthesis and antitumor activity of bile acid-polyamine-nucleoside conjugates[J].Bioorg Med Chem Lett,2007,17(11):2983-2986.
[5]PASCHKE R,KALBITZ J,PAETZ C.Novel spacer linked bile acid-cisplatin compounds as a model for specific drug delivery,synthesis and characterization[J].Inorg Chim Acta,2000,304(2):241-249.
[6]SREEKANTH V,BANSAL S,MOTIANI R K,et al.Design,synthesis,and mechanistic investigations of bile acid-tamoxifen conjugates for breast cancer therapy[J].Bioconjugate Chem,2013,24(9):1468-1484.
[7]胡祥正,陆伟.胆酸甲酯羟基酰化反应活性研究[J].化学研究,2006,17:44-46.
[8]DAVIS A P.Cheminform Abstract:bile acid scaffolds in supramolecular chemistry:the interplay of design and synthesis[J].Cheminform,2009,40(4):2106-2122.
[9]HE J,LI J,ZHANG Y M,et al.Simultaneous determination of four major conjugated cholic acids in dry bile of sus scrofa domestica brisson by MEKC[J].Chromatogr Sci Ser,2010,71(9/10):947-951.
[10]ZHAO Y,ZHONG Z Q.Oligomeric cholates:amphiphilic foldamers with nanometer-sized hydrophilic cavities[J].J Am Chem Soc,2005,127(50):17894-17901.
[11]GIOFRE S,ROMEO R,CHIACCHIO U,et al.Phosphonated N,O-nucleosides:synthesis and biological evaluation[J].Mini-Rev Org Chem,2015,12(9):249-257.
[12]KATZ M J,MOON S Y,MONDLOCH J E,et al.Exploiting parameter space in MOFs:a 20-fold enhancement of phosphate-ester hydrolysis with UiO-66-NH2[J].Chem Sci,2015,6:2286-2291.
[13]BUBENIK M,REJ R,NGUYEN-BA N,et al.Novel nucleotide phosphonate analogues with potent antitumor activity[J].Cheminform,2002,34(9):3063-3066.
[14]RAO XP,SONG ZQ,HE L.Synthesis and antitumor activity of novelα-aminophosphonates from diterpenic dehydroabietylamine[J].Heteroat Chem,2008,19(5):512-516.
[15]TEXIER-BOULLET F,FOUCAUD A.A convenient synthesis of dialkyl 1-hydroxyalkanephosphonates using potassium or caesium fluoride without solvent[J].Synthesis,1982,1982(2):165-166.