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.

OBJECTIVE To design and synthesize a novel set of 20 stilbenenitrile sulfonamide derivatives based on combretastatin A-4（CA-4） and ABT-751 possessing high potency and low toxicity. METHODS The anti-proliferation activity and toxicity of these compounds were evaluated by MTT assay with five kinds of cancer cell lines and two normal cell lines, and the candidates were selected out. Then the cell cycle and apoptosis assays were carried out and the effect of the candidate on the expressions of VEGF and MMP-9 were evalusted. RESULTS A majority of compounds demonstrated potent anti-proliferation activity in five kinds of tumor cell lines. Particularly, the compound 8h exhibited the most potent anticancer activity in MCF-7 cancer cell line(IC 50 =8.7 μmol·L -1 ), but low toxicity on normal human breast cell MCF-10A(IC 50 ＞100 μmol·L -1 ), which showed a selectivity. Simultaneously, compound 8h inhibited the proliferation of MCF-7 by arresting at the G 2 /M phase. In addition, the inhibition of VEGF expression of compound 8h was concentration-dependent under hypoxia and normoxia and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. Synchronously, the inhibition of MMP-9 expression of compound 8h was concentration-dependent and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. CONCLUSION Compound 8h are worthy of further study as an efficient and low-toxicity anti-breast cancer drug.

OBJECTIVE To obtain novel candidate compounds with safety and good anticancer activity. METHODS Using substituted acetophenone and substituted aromatic aldehydes as the starting materials, chalcone was synthesized by Claisen-Schmidt condensation reaction, and then 17 compounds were synthesized by reacting with hydrazine hydrate and chloroacetyl chloride successively. The structures of these compounds were confirmed and their anticancer and antibacterial activities were detected in vitro. RESULTS The results of biological activity test showed that the compounds 4a-4h had good anticancer activity in vitro, and exhibited different inhibitory activity against cancer cells of different origin. The IC50 values of compound 4a against human colorectal cancer cell HCT116 was 1. 1μmol·L–1. The IC50 values of compound 4c against human hepatoma cell BEL-7402 was 4. 8 μmol·L–1.The IC50 values of compound 4b against human cervical cancer cell HeLa was 13. 2 μmol·L–1, and the inhibitory effect was stronger. CONCLUSION Some of the synthesized target compounds showed good anticancer activity and cell selectivity,which has the potential to develop new anticancer drugs.

为了寻找安全且具有良好抗菌效果的防腐剂,本文设计合成了8个厚朴酚衍生物,并评价其抗菌活性及对四种正常细胞的毒性,同时测定其水溶性.结果表明,化合物3a对耐甲氧西林金黄色葡萄球菌3167与白色念珠球菌7535等6种菌的抗菌活性明显优于厚朴酚,三种化合物2a、5a及8a的抗菌效果优于或相当于厚朴酚.7个化合物对正常细胞的毒性很低,化合物5a等5个化合物的水溶性高于厚朴酚.作为天然防腐剂,化合物3a具有值得进一步研究的价值.

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.