Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, USA.
Bioorg Med Chem. 2009 Oct 15;17(20):7145-55. doi: 10.1016/j.bmc.2009.08.066. Epub 2009 Sep 6.
The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are 'composites' of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (>6 carbons) possess lower anti-top1 activity than their smaller counterparts (2-4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a 'universal' top1 inhibitor SAR.
芳香酶拓扑异构酶 I（top1）抑制剂为新型癌症化疗药物的开发提供了有前景的支架。它们是喜树碱和茚并异喹啉 top1 抑制剂的“复合物”。有趣的是，在芳香酶和茚并异喹啉之间观察到了一些结构-活性关系（SAR）的重叠。对于这两类化合物，将某些极性基团放置在杂芳环系统的相似区域可提高 top1 抑制和抗增殖活性。已经制备了一系列在 14 位用各种长度的二氨基链烷取代的水溶性芳香酶。这些化合物都具有相似的抗增殖效力，但观察到一个普遍趋势：具有较长二氨基链烷取代基（>6 个碳原子）的芳香酶比其较小的对应物（2-4 个碳原子）具有更低的抗 top1 活性，可能是由于不利的疏水相互作用。在茚并异喹啉中也注意到了这种趋势，揭示了额外的 SAR 重叠，这支持了存在“通用”top1 抑制剂 SAR 的假设。
