Combretastatin A-4 (CA-4) is a potent tubulin polymerisation inhibitor. However, the clinical application of CA-4 is limited owing to its low aqueous solubility and the easy conversion of the olefin double bond from the more active cis- to the less active trans-configuration. Several structural modifications were investigated to improve the solubility of CA-4 derivatives. Among the compounds we synthesized, the kinetic solubility assay revealed that the solubility of compounds containing a piperazine ring increased the most, and the solubility of compounds 12a1, 12a2, 15 and 18 was increased 230–2494 times compared with that of the control compound (Z)-3-(4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (9a). In addition, these synthesised stilbene nitriles had high anticancer cell (AGS, BEL-7402, MCF-7, and HCT-116) selectivity over L-02 and MCF-10A normal cells while maintaining micromolar activity against cancer cells. The most cytotoxic compound is 9a, and the IC50 value is 20 nM against HCT-116 cancer cells. Preliminary studies indicated that compound 12a1 had excellent plasma stability and moderate binding to rat plasma proteins, suggesting it is a promising lead compound for the development of an anticancer agent.

The amide intermediates 5a similar to 5j were prepared by acylation, which used 2-thiopheneethylamine and several self-synthetic chalcone acids as starting materials. Then ten dihydrothiophenopyridine-chalcone derivatives 6a similar to 6j which haven't been reported before were synthesized by Bischer-Napieralski cyclization reaction from the intermediates. In addition, two new thiophenopyridine-chalconone derivatives 7a and 7b were obtained by further dehydrogenation. The anti-cancer activity and safety in vitro of 11 kinds of cells were evaluated by methyl thiazolyl tetrazolium (MTT) assay. The results indicated that the compounds 6a (p-F), 6d (o-Br) and 6h (m-OCH3) exerted better anticancer activity against HeLa and SGC-7901 cells than taxol. When treating cells for a short time (<4 h), 6j (3,4,5-(OCH3)(3)) showed strong anticancer activity against MCF-7 cancer cell but displayed little toxicity on normal breast cell MCF-10A. Hence, 6j deserves further research and exploitation.

刘雅雪 陈志豪 秦 巍 田玉顺 * (延边大学药学院 长白山天然药物研究教育部重点实验室 吉林延吉 133002) 摘要 以 2-噻吩乙胺与自制的查尔酮酸进行酰化反应得到酰胺类中间体 5a～5j, 经 Bischer-Napieralski 环合反应合成了 10 个未见报道的二氢噻吩并吡啶-查尔酮衍生物 6a～6j, 再经去氢反应获得 2 个噻吩并吡啶-查尔酮衍生物 7a 和 7b.通 过噻唑蓝(MTT)法对 11 种细胞进行体外抗癌活性及安全性测试.

白藜芦醇(RSV)是存在于浆果、葡萄、虎杖等多种植物中的一种二苯乙烯结构,是A环的C3及C5位和B环的C4'位分别有酚羟基的2个苯环通过一个乙烯基相连的结构(图1中的RSV).因2个苯环间有乙烯基,所以白藜芦醇具有2种几何异构体,即cis-与trans-.天然的白藜芦醇一般是trans-构型(图1中的RSV所示构型),当trans-构型被紫外线或可见光照射时可发生光异构化现象而生成cis-构型,但cis-构型不稳定且无市售的产品[1-2].白藜芦醇在抗炎、抗癌和抗氧化等诸多方面具有广泛的功效[3].因天然白藜芦醇具有较差的水溶性、生物利用度、化学稳定性及活性,且它的代谢速度较快,所以很多学者就着手研究它的衍生物以寻找理想的化合物并已发现诸多类似物,如反式-3,4,5,4'-四甲氧基二苯乙烯等[4-5].虽然白藜芦醇及其类似物在实验室阶段具有良好的功效,但尚未开发出有特定功效的药物,目前市售的还是以白藜芦醇保健品类为主.随着科技的发展,不断涌现出新的靶点基因和蛋白质,而且测定技术也越来越先进,这对发现药物的新作用机制方面有重要意义.本文对白藜芦醇及其衍生物的药物开发可能性的研究进展进行了综述.

[目的]获得安全并具有良好抗肝癌细胞活性的新型候选化合物.[方法]合成一系列含芳基酰胺考布他汀衍生物并验证其结构,采用MTT法检测所合成的化合物对人肝癌细胞株BEL-7402和HepG-2及人正常肝细胞L-02的抗增殖活性.[结果]所合成的一系列含芳基酰胺考布他汀衍生物中多数化合物对人肝癌细胞株BEL-7402表现出良好的抑制活性,其中(Z)-N-(4-(2-氰基-2-(3,4,5-三甲氧基苯基)乙烯基)苯基)-3,4,5-三甲氧基苯甲酰胺(8g)显示出最佳的抗肝癌细胞活性,且对人正常肝细胞的毒性较小.[结论]所合成的化合物8g具有良好的抗肝癌细胞活性.

以4-三氟甲基苯甲酸和3,4,5-三甲氧基苯甲酸为原料合成出2-(4-(三氟甲基)苯基)乙腈和2-(3,4,5-三甲氧基苯基)乙腈,将其作为中间体和几种醛类合成一系列含4-三氟甲基及3,4,5-三甲氧基二苯乙烯腈衍生物.所合成的化合物通过氢谱、碳谱与高分辨质谱进行表征后用MTT法在12种细胞上测得其细胞增殖抑制率,其中(Z)-3-(4-丙氧基苯基)-2-(3,4,5-三甲氧基苯基)丙烯腈显示最好的抗癌活性及选择性抑制活性,经进一步研究发现通过抑制细胞迁移与抑制集落形成达到抗癌效果,具有进一步开发研究的价值.