Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
Pharm Res. 2012 Nov;29(11):3033-9. doi: 10.1007/s11095-012-0816-3. Epub 2012 Jul 20.
To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents.
Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel.
Pyrrolo[3,2-d]pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI(50)) inhibitor of 8 tumor cell lines.
We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization.
研究区域异构变化对先前报道的水溶性、秋水仙碱结合位点、微管解聚剂生物活性的影响。
设计并合成了 9 种吡咯并[3,2-d]嘧啶。评估了各种取代基的重要性。研究了它们引起细胞微管解聚、抑制 MDA-MB-435 肿瘤细胞增殖和抑制秋水仙碱与微管蛋白结合的能力。其中一种化合物还在国家癌症研究所临床前 60 细胞系面板中进行了评估。
吡咯并[3,2-d]嘧啶类似物比其吡咯并[2,3-d]嘧啶区域异构体更有效。我们确定了对细胞增殖具有亚微摩尔效力的化合物。构效关系研究深入了解了对活性至关重要的取代基和提高活性的取代基。在 NCI 60 细胞系中测试的化合物是 8 种肿瘤细胞系的 2 位数字纳摩尔（GI（50））抑制剂。
我们已经确定了取代的吡咯并[3,2-d]嘧啶是水溶性秋水仙碱结合位点微管解聚剂。这些化合物可作为进一步优化的先导化合物。
