Siebert Agnieszka, Gensicka Monika, Cholewinski Grzegorz, Dzierzbicka Krystyna
Faculty of Chemistry, Department of Organic Chemistry, Gdansk University of Technology, G. Narutowicza St 11/12, 80-233 Gdansk, Poland.
Anticancer Agents Med Chem. 2016;16(8):942-960. doi: 10.2174/1871520616666160204111832.
Combretastatin A-4 (CA-4) is a natural product, which consists of two phenyl rings, linked by an ethylene bridge. CA-4, inhibitor of polymerization of tubulin to microtubules, possesses a strong antitumor and anti-vascular properties both in vitro and in vivo. Previous studies showed that disodium phosphate salt of CA-4, a water-soluble prodrug is well tolerated at therapeutically useful doses. However, it should be noted that the cis-configuration of the double bond and the 3,4,5-trimethoxy group on ring A is necessary for the biological activity of CA-4. Structure of CA-4 renders the compound readily susceptible to isomerization, which reduces the potency and bioavailability. To circumvent this problem, a lot of scientists in the world synthesized a series of cis-restricted CA-4 analogs, where the double bond has been replaced by introduction of non-heterocyclic groups or heterocyclic groups like β -lactam and oxadiazole. This paper reviews the most important approaches in analogs of combretastatin synthesis and presents structure-reactivity relationships for these compounds.
康普瑞他汀A-4（CA-4）是一种天然产物，由两个苯环通过一个亚乙基桥相连组成。CA-4是微管蛋白聚合成微管的抑制剂，在体外和体内均具有强大的抗肿瘤和抗血管生成特性。先前的研究表明，CA-4的磷酸二钠盐，一种水溶性前药，在治疗有效剂量下耐受性良好。然而，需要注意的是，双键的顺式构型以及A环上的3,4,5-三甲氧基对于CA-4的生物活性是必需的。CA-4的结构使该化合物易于发生异构化，从而降低了效力和生物利用度。为了解决这个问题，世界上许多科学家合成了一系列顺式受限的CA-4类似物，其中双键已通过引入非杂环基团或杂环基团（如β-内酰胺和恶二唑）来取代。本文综述了康普瑞他汀类似物合成中最重要的方法，并介绍了这些化合物的结构-反应性关系。
