Duflos Alain, Kruczynski Anna, Barret Jean-Marc
Division de Chimie Médicinale V, Centre de Recherche Pierre Fabre 81106-Castres, France.
Curr Med Chem Anticancer Agents. 2002 Jan;2(1):55-70. doi: 10.2174/1568011023354452.
The clinical interest of Vinca alkaloids was clearly identified as early as 1965 and so this class of compounds has been used as anticancer agents for more than 30 years. Today, two natural compounds, vinblastine and vincristine and two semi-synthetic derivatives, vindesine and vinorelbine, have been registered and thus Vinca alkaloids can be considered to represent a chemical class of definite utility in cancer chemotherapy. Today, relatively few groups actively research in the chemistry of Vinca alkaloids. However, using superacidic chemistry, a new family of such compounds was synthesised and vinflunine, a difluorinated derivative, was selected for clinical testing. A consideration of the pharmacological data relating to these new derivatives appears to reveal a lack of any marked correlation between in vitro and in vivo results. Furthermore, structure/activity relationships have failed to assist the chemist in the rational design. Such rational design of new derivatives is limited by the fact that the Vinca binding site(s) on tubulin and the exact mechanism(s) of action of Vinca alkaloids remain unclear. Nevertheless, the preclinical evaluations of the new derivative vinflunine have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identified properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semi-synthetic Vinca alkaloids. Thus, Vinca alkaloids remain a drug family with a continuing interest for future anticancer therapy.
早在1965年，长春花生物碱的临床价值就已得到明确确认，因此这类化合物作为抗癌药物已使用了30多年。如今，两种天然化合物长春碱和长春新碱以及两种半合成衍生物长春地辛和长春瑞滨已获注册，因此长春花生物碱可被视为在癌症化疗中具有一定实用价值的一类化学物质。如今，积极从事长春花生物碱化学研究的团队相对较少。然而，利用超强酸化学合成了这类化合物的一个新家族，并选择了一种二氟化衍生物长春氟宁进行临床试验。对这些新衍生物相关药理数据的考量似乎显示，体外和体内结果之间缺乏任何明显的相关性。此外，构效关系未能帮助化学家进行合理设计。新衍生物的这种合理设计受到以下事实的限制：微管蛋白上长春花生物碱的结合位点以及长春花生物碱的确切作用机制仍不清楚。尽管如此，新衍生物长春氟宁的临床前评估已经表明，除体内实验外，还可以提出某些体外试验，以便更合理地筛选新一代长春花生物碱。此外，最近的研究表明，某些新发现的特性，如抗血管生成活性，可能会扩大天然和半合成长春花生物碱的治疗用途。因此，长春花生物碱仍然是一个对未来抗癌治疗持续具有吸引力的药物家族。
