Thammathong Joshua, Chisam Kaylee B, Tessmer Garrett E, Womack Carl B, Sidrak Mario M, Weissmiller April M, Banerjee Souvik
Department of Chemistry, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States.
Department of Biology, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States.
ACS Med Chem Lett. 2023 Aug 25;14(9):1284-1294. doi: 10.1021/acsmedchemlett.3c00298. eCollection 2023 Sep 14.
Targeting the colchicine binding site on tubulin is a promising approach for cancer treatment to overcome the limitations of current tubulin polymerization inhibitors. New classes of colchicine binding site inhibitors (CBSIs) are continually being uncovered; however, balancing metabolic stability and cellular potency remains an issue that needs to be resolved. Therefore, we designed and synthesized a series of novel fused imidazopyridine and -pyrazine CBSIs and evaluated their cellular activity, metabolic stability, and tubulin-binding properties. Evidence shows that the imidazo[1,2-]pyrazine series are effective against neuroblastoma cell lines marked by amplification. Further assessment shows that a combination of an imidazo[1,2-]pyrazine core with a trimethoxyphenyl ring D results in the highest cellular activity and binding characteristics compared with a dichloromethoxyphenyl or difluoromethoxyphenyl ring D. However, the metabolic stability of compounds with a dichloromethoxyphenyl or difluoromethoxyphenyl ring D is significantly higher than that of those containing a trimethoxyphenyl ring D, suggesting that improved metabolic stability is achieved with a moderate impact on potency.
靶向微管蛋白上的秋水仙碱结合位点是一种很有前景的癌症治疗方法，可克服当前微管蛋白聚合抑制剂的局限性。新型秋水仙碱结合位点抑制剂（CBSIs）不断被发现；然而，平衡代谢稳定性和细胞活性仍然是一个需要解决的问题。因此，我们设计并合成了一系列新型稠合咪唑并吡啶和吡嗪CBSIs，并评估了它们的细胞活性、代谢稳定性和微管蛋白结合特性。证据表明，咪唑并[1,2 -]吡嗪系列对以扩增为特征的神经母细胞瘤细胞系有效。进一步评估表明，与二氯甲氧基苯基或二氟甲氧基苯基环D相比，咪唑并[1,2 -]吡嗪核心与三甲氧基苯基环D的组合具有最高的细胞活性和结合特性。然而，具有二氯甲氧基苯基或二氟甲氧基苯基环D的化合物的代谢稳定性明显高于含有三甲氧基苯基环D的化合物，这表明在对活性有适度影响的情况下实现了代谢稳定性的提高。
