Pouli Nicole, Marakos Panagiotis
University of Athens, Department of Pharmacy, Division of Pharmaceutical Chemistry, Panepistimiopolis-Zografou, Athens 15771, Greece.
Anticancer Agents Med Chem. 2009 Jan;9(1):77-98. doi: 10.2174/187152009787047699.
Xanthones have been isolated from several natural sources, mainly belonging in Guttiferae and Gentianaceae families as secondary plant metabolites and many of them are endowed with diverse pharmacological properties. We have focused in the study of cytotoxic fused xanthone derivatives, having in mind that some furano- and pyranoxanthone natural products are particularly interesting, in terms of cytotoxic potency and novelty in their mechanism of action and could serve as lead compounds for the development of clinically effective anticancer agents. In this review, a general classification has been attempted based on the type of ring fusion, in such a way that natural compounds as well as synthetic derivatives are discussed. The furanoxanthone psorospermin is a highly promising isolated xanthone derivative exhibiting significant cytotoxicity through a novel mechanism of action, being an irreversible topoisomerase II poison and it was selected for further development as an antineoplastic agent. An important number of pyranoxanthones have been synthesized using as lead compound the acridone alkaloid acronycine. Adducts on the double bond of these compounds provided cytotoxic derivatives possessing cell-cycle selectivity. The synthesis of pyranoxanthones bearing aminosubstituted side-chains resulted in compounds that exhibit markedly improved cytotoxicity towards leukemic and solid tumor cell lines. Azabioisosters of the aminoderivatives exhibit solid tumor selectivity whereas additional pyrazole or/and benzene ring fusion has been incorporated into the xanthone skeleton and resulted in compounds with promising activity, which retain full antiproliferative activity against P-glycoprotein-overexpressing cells. Gambogic acid, a highly effective anticancer drug candidate with low toxicity to normal tissue, together with structurally related representative analogues are also mentioned.
呫吨酮已从多种天然来源中分离出来，主要属于藤黄科和龙胆科，是植物的次生代谢产物，其中许多具有多种药理特性。我们专注于细胞毒性稠合呫吨酮衍生物的研究，考虑到一些呋喃并呫吨酮和吡喃并呫吨酮天然产物在细胞毒性效力及其作用机制的新颖性方面特别有趣，可作为开发临床有效抗癌药物的先导化合物。在这篇综述中，我们尝试根据环稠合类型进行总体分类，以便对天然化合物和合成衍生物进行讨论。呋喃并呫吨酮补骨脂苦素是一种非常有前景的分离呫吨酮衍生物，通过一种新的作用机制表现出显著的细胞毒性，它是一种不可逆的拓扑异构酶II毒物，并被选作进一步开发的抗肿瘤药物。已经以吖啶酮生物碱山油柑碱为先导化合物合成了大量的吡喃并呫吨酮。这些化合物双键上的加合物提供了具有细胞周期选择性的细胞毒性衍生物。带有氨基取代侧链的吡喃并呫吨酮的合成产生了对白血病和实体瘤细胞系表现出明显增强细胞毒性的化合物。氨基衍生物的氮杂生物电子等排体表现出实体瘤选择性，而额外的吡唑或/和苯环稠合已被引入呫吨酮骨架中，并产生了具有有前景活性的化合物，这些化合物对过表达P-糖蛋白的细胞保留了完全的抗增殖活性。藤黄酸是一种对正常组织毒性低的高效抗癌候选药物，同时也提到了与其结构相关的代表性类似物。
