Garuti Laura, Roberti Marinella, Pizzirani Daniela
Department of Pharmaceutical Science, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.
Curr Med Chem. 2008;15(6):573-80. doi: 10.2174/092986708783769722.
Inhibition of Cdc25 phosphatases is a strategy for the discovery and development of novel anticancer agents targeting the cell cycle. A number of potent small molecule Cdc25 inhibitors have been identified. They are derived from different chemical classes; the most potent and selective derivatives are quinones. The electrophilic properties of quinones suggest the possibility of inducing a sulphydryl arylation of a cysteine in the enzyme active site. It is also possible that inhibition is due to redox cycling activity and production of ROS. Thus, oxidation of the thiolate form of cysteine occurs, leading to inactivation of enzymatic activity. Many of these inhibitors are active on all three Cdc25 phosphatases, cause cell cycle arrest and inhibit the growth of several human tumor cell lines. The possibility of toxicities induced by ROS, prompted the search for non-quinoid antagonists. It is not yet clear how these compounds bind within the enzyme's active site. Generally, electrophilic moieties able to trap the catalytic cysteine play an important role. Another strategy for identifying Cdc25 inhibitors is the development of compounds able to interact with the conserved loop region instead of phosphate.. In this review a summary of the most interesting Cdc25 inhibitors is given together with their biological activity. SAR studies concerning the importance of some structural features will be described.
抑制Cdc25磷酸酶是发现和开发靶向细胞周期的新型抗癌药物的一种策略。已经鉴定出许多强效小分子Cdc25抑制剂。它们源自不同的化学类别；最有效和选择性最强的衍生物是醌类。醌类的亲电特性表明有可能在酶活性位点诱导半胱氨酸的巯基芳基化。抑制作用也可能是由于氧化还原循环活性和活性氧的产生。因此，半胱氨酸的硫醇盐形式发生氧化，导致酶活性失活。这些抑制剂中的许多对所有三种Cdc25磷酸酶均有活性，导致细胞周期停滞并抑制几种人类肿瘤细胞系的生长。活性氧诱导毒性的可能性促使人们寻找非醌类拮抗剂。目前尚不清楚这些化合物如何在酶的活性位点内结合。一般来说，能够捕获催化性半胱氨酸的亲电部分起着重要作用。鉴定Cdc25抑制剂的另一种策略是开发能够与保守环区域而非磷酸相互作用的化合物。在这篇综述中，给出了最有趣的Cdc25抑制剂及其生物学活性的总结。将描述有关一些结构特征重要性的构效关系研究。
