Laboratory for Drug Design & Synthesis, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Bioorg Med Chem. 2013 Feb 1;21(3):618-31. doi: 10.1016/j.bmc.2012.11.050. Epub 2012 Dec 11.
Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC(50) values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4',5'-f][1,3]diazepine structural skeleton of the lead compound 1.
基于与已知靶点之一——人 RNA 解旋酶（hDDX3）的分子建模研究，对 5:7-稠合环扩大型核苷（RENs）进行了司法结构修饰，得到了先导、新型的 5:7-5-稠合三环杂环（1）。后者对筛选出的多种癌细胞系表现出有前景的广谱体外抗癌活性。本文描述了我们对该先导化合物进行的系统（尽管有限）的构效关系（SAR）研究，该研究产生了许多具有广谱体外抗癌活性的类似物，对肺癌、乳腺癌、前列腺癌和卵巢癌细胞系具有活性，特别是化合物 15i、15j、15m 和 15n，它们对 IC50 值的范围在亚毫摩尔到微摩尔之间，值得进一步探索。SAR 数据还使我们能够提出一个暂定的 SAR 模型，用于未来的 SAR 研究，以最终实现基于先导化合物 1 的二咪唑并[4,5-d:4',5'-f][1,3]二氮杂环戊烯结构骨架的最佳活性和最小毒性的抗癌化合物。
