3-苯基-3-吡咯基戊烷类化合物的合成及体外生物活性  

Synthesis and in vitro biological activity of 3-phenyl-3-pyrrolylpentane derivatives

作　　者：许梦[1] 葛执信[1] 郝玫茜 张灿[1] 

机构地区：[1]中国药科大学新药研究中心,江苏省代谢性疾病药物重点实验室,南京210009

出　　处：《中国药科大学学报》2016年第1期30-37,共8页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81273468)~~

摘　　要：以非开环甾体类维生素D受体(VDR)激动剂LG190155为先导物,通过结构改造设计合成了一系列3-苯基-3-吡咯基戊烷类化合物。通过测定目标化合物对HL-60细胞的促分化能力间接测定其对VDR的激动能力。结果表明,化合物13a,13c,13d,13h,13i,13j表现出较好的HL-60促分化活性(EC_(50)<50μmol/L),提示这6个化合物具有较好的VDR激动能力。其中以化合物13j的促分化活性最高(EC_(50)=0.10μmol/L),且优于先导化合物LG190155。采用MTT法评价目标化合物对VDR高表达的肿瘤细胞(人前列腺癌细胞PC-3、人乳腺癌细胞MCF-7、人结肠癌细胞Caco-2、人肝癌细胞Hep G2)和人肝正常细胞(L02)的增殖抑制活性。结果表明,化合物13a在Hep G2细胞株中的增殖抑制活性最好(IC_(50)=0.11μmol/L),且对普通肝细胞L02的抑制作用较低(IC_(50)=15.24μmol/L),说明化合物13a对肝肿瘤细胞具有一定选择性。此外还发现所合成化合物的促分化活性与抑制增殖活性成正相关。A new series of 3-phenyl-3-pyn-olylpentane derivatives were synthesized through modifying the struc- ture of the lead compound LG19055, which has been the first nonsecosteroidal vitamin D receptor（VDR） agonist reported. The VDR-agonistic ability of target compounds was measured indirectly by evaluating the differentiation ability of HL-60 cell. The results showed that compounds 13a, 13c, 13d, 13h, 13i, 13j had excellent VDR-agonis- tie ability（ EC50 〈 50μmol/L）, especially for compound 13j（ EC50 = 0. 10 μmol/L）, which was more potential than that of lead compound LG190155. Their proliferation inhibitory activities in vitro were evaluated by MTF assay in MCF-7, PC-3, Caco-2, HepG2 and L02 cell lines. Compound 13a exhibited significant inhibitory effects on HepG2 cell line（ IC50 = 0. 11μmol/L）. Moreover, the inhibitory effect of compound 13a on non-tumor liver IA32 cell line was relatively weak（ IC50 = 15.24μmol/L）, suggesting that compound 13a had selective inhibitory effects on liver cancer cells. Additionally, HL-60 cell differentiation-inducing activity and the inhibitory effect of cancer cells were positively related.

关 键 词：3-苯基-3-吡咯基戊烷衍生物 非开环甾体类激动剂 合成 维生素D受体激动活性 肿瘤 增殖抑制 

分 类 号：R914.5[医药卫生—药物化学] R96[医药卫生—药学]