Chen Xiaoyan, Winstead Angela, Yu Hongtao, Peng Jiangnan
Department of Chemistry, Morgan State University, Baltimore, MD 21251, USA.
Cancers (Basel). 2021 Feb 22;13(4):920. doi: 10.3390/cancers13040920.
Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of . In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22-C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides.
微管稳定剂，如紫杉醇、多西他赛和卡巴他赛，在过去几十年里一直是临床上治疗多种癌症最常用的化疗药物之一。限制它们在临床实践中使用的一个问题是其内在和获得性耐药性，这在大多数抗癌化疗药物中都很常见。紫杉烷内酯是从几种植物种属的根中分离出的一类新型微管稳定剂。在早期研究中，紫杉烷内酯对间期和有丝分裂微管的作用与紫杉醇和 laulimalide 不同，提示其独特的作用机制。这促使通过鉴定天然来源的次要成分和半合成来探索具有各种功能的新型紫杉烷内酯。对新型高效紫杉烷内酯的实验表明，紫杉烷内酯具有与微管共价结合的独特机制。对与微管蛋白结合的紫杉烷内酯 AJ 晶体的 X 射线衍射分析表明，共价结合位点在β-微管蛋白 D226 处。紫杉烷内酯在体外和体内都能规避紫杉烷类药物耐药性的所有三种机制。为了提高活性，进行了半合成的结构修饰，并基于天然和半合成的紫杉烷内酯分析了构效关系（SARs）。C22-C23 环氧化物可通过 C22 与 D226 的羧基共价连接，显著提高紫杉烷内酯的抗增殖效力。在过去几年里，对这类微管稳定剂作用机制的理解取得了很大进展。本综述总结了紫杉烷内酯的结构多样性、构效关系（SARs）、作用机制和体内活性。
