Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, Lisboa 1649- 003, Portugal.
CBiOS - Universidade Lusofona de Humanidades e Tecnologias, Campo Grande 376, Lisboa 1749-024, Portugal.
Curr Pharm Des. 2018;24(36):4270-4311. doi: 10.2174/1381612825666190111123959.
The growing incidence of cancer, the toxic side-effects associated with conventional chemotherapeutic agents and the development of multidrug resistance (MDR) drive the search for novel and more effective drugs with multi-target activity and selectivity towards cancer cells. Stilbenes are a group of naturally occurring phenolic compounds of plant origin derived from the phenylpropanoid pathway that may exist as cis- or trans-isomers. Although the trans-isomer is the more common and stable configuration, resveratrol being a representative compound, cis-stilbenes are potent cytotoxic agents that bind to and inhibit tubulin polymerization, destabilizing microtubules. This review summarizes the chemistry and biological evaluation of cytotoxic stilbenes and their synthetic derivatives as promising antimitotic leads for cancer therapy, focusing on the most potent compounds, the combretastatins. Combretastatins isolated from the South African bushwillow Combretum caffrum are among the most potent antimitotic and vascular disrupting agents (VDAs) of natural origin. Preclinical studies have demonstrated their potent antitumor effects in a wide variety of tumors, both in vitro and in vivo, being currently under evaluation in phase 2 and phase 3 clinical trials for several types of solid tumors. Topics covered herein include synthetic medicinal chemistry, modes of action, structure-activity relationships (SAR), preclinical and clinical studies as VDAs in cancer therapy, either as single agents or in combination with cytotoxic anticancer drugs, antiangiogenic agents, or radiation therapy, and development of appropriate formulations based on nanocarriers (e.g., liposomes, nanoemulsions, polymeric, lipid and ceramic nanoparticles, carbon nanotubes) for improved bioavailability and targeted delivery of combretastatins to the tumor vasculature.
癌症发病率不断上升，与传统化疗药物相关的毒性副作用以及多药耐药性（MDR）的发展，促使人们寻找具有多靶点活性和对癌细胞选择性的新型、更有效的药物。二苯乙烯类化合物是一组天然存在的植物酚类化合物，来源于苯丙素途径，可能存在顺式或反式异构体。尽管反式异构体更为常见且稳定，但作为代表性化合物的白藜芦醇，顺式二苯乙烯是有效的细胞毒性剂，可与微管蛋白聚合结合并抑制其聚合，从而破坏微管的稳定性。本综述总结了细胞毒性二苯乙烯及其合成衍生物的化学和生物学评价，作为癌症治疗有前途的抗有丝分裂先导化合物，重点介绍了最有效的化合物——康普瑞汀。从南非布什威柳 Combretum caffrum 中分离出的康普瑞汀是天然来源的最有效抗有丝分裂和血管破坏剂（VDA）之一。临床前研究表明，它们在各种肿瘤中具有强大的抗肿瘤作用，无论是在体外还是体内，目前正在进行 2 期和 3 期临床试验，用于多种实体瘤的治疗。本文涵盖的主题包括合成药物化学、作用机制、构效关系（SAR）、作为 VDA 治疗癌症的临床前和临床研究，无论是作为单一药物还是与细胞毒性抗癌药物、抗血管生成剂或放射治疗联合使用，以及基于纳米载体（例如脂质体、纳米乳液、聚合物、脂质和陶瓷纳米粒子、碳纳米管）开发适当的制剂，以提高康普瑞汀的生物利用度和靶向递送至肿瘤血管。
