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开发具有改善水溶性的 Combretastatin A-4 类似物作为潜在的抗癌剂。

Development of Combretastatin A-4 Analogues as Potential Anticancer Agents with Improved Aqueous Solubility.

机构信息

Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China.

出版信息

Molecules. 2023 Feb 10;28(4):1717. doi: 10.3390/molecules28041717.

DOI:10.3390/molecules28041717
PMID:36838705
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9963121/
Abstract

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 to the less active -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 ()-3-(4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (). 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 , and the IC50 value is 20 nM against HCT-116 cancer cells. Preliminary studies indicated that compound 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.

摘要

Combretastatin A-4（CA-4）是一种有效的微管聚合抑制剂。然而，由于其低水溶性和容易将双键从更活跃的顺式构型转化为不活跃的反式构型，CA-4 的临床应用受到限制。我们研究了几种结构修饰来提高 CA-4 衍生物的溶解度。在我们合成的化合物中，动力学溶解度测定表明，含有哌嗪环的化合物的溶解度增加最多，化合物 12a1、12a2、15 和 18 的溶解度比对照化合物（）-3-（4-氨基苯基）-2-（3,4,5-三甲氧基苯基）丙烯腈（）增加了 230-2494 倍。此外，这些合成的二苯乙烯腈对 AGS、BEL-7402、MCF-7 和 HCT-116 癌细胞具有高抗癌细胞（AGS、BEL-7402、MCF-7 和 HCT-116）选择性，同时对正常细胞 L-02 和 MCF-10A 保持微摩尔活性。最具细胞毒性的化合物是 ，对 HCT-116 癌细胞的 IC50 值为 20 nM。初步研究表明，化合物 具有优异的血浆稳定性和适度结合大鼠血浆蛋白，表明它是开发抗癌药物的有前途的先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/562ba89ba691/molecules-28-01717-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/f004e0e354b5/molecules-28-01717-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/8ead27ea7f59/molecules-28-01717-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/b23b72645759/molecules-28-01717-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/f95f27194ff1/molecules-28-01717-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/c67abb9d3692/molecules-28-01717-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/416f6aef4dc2/molecules-28-01717-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/562ba89ba691/molecules-28-01717-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/f004e0e354b5/molecules-28-01717-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/8ead27ea7f59/molecules-28-01717-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/b23b72645759/molecules-28-01717-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/f95f27194ff1/molecules-28-01717-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/c67abb9d3692/molecules-28-01717-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/416f6aef4dc2/molecules-28-01717-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bb/9963121/562ba89ba691/molecules-28-01717-g005.jpg

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