Kumar Atul, Gupta Garima, Bishnoi Ajay Kumar, Saxena Ruchi, Saini Karan Singh, Konwar Rituraj, Kumar Sandeep, Dwivedi Anila
Academy of Scientific & Innovative Research (AcSIR), New Delhi, India; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India.
Bioorg Med Chem. 2015 Feb 15;23(4):839-48. doi: 10.1016/j.bmc.2014.12.037. Epub 2014 Dec 23.
We report herein the design and synthesis of bioisosteres of spirooxindole (MI-63/219), a small-molecule inhibitors of the MDM2-p53 interaction as anti-breast cancer agents. Compound 5b has been exhibiting significant anti-proliferative activity in nude mice bearing MCF-7 xenograft tumor. The compound 5b was found to act via modulation of MDM2 and p53 expression in breast cancer cells expressing wild type p53. Compound 5b stimulated p53 activation, caused modulation of downstream effectors p21, pRb, and cyclin D1 which regulate cell cycle. Thus, compound triggered G1-S phase cell cycle arrest, which was evident by flow cytometric analysis of treated breast cancer cells. Thus, compound 5b restores the p53 function, which triggers molecular events consistent with cell cycle arrest at G1/S phase.
我们在此报告了螺环氧化吲哚（MI-63/219）生物电子等排体的设计与合成，螺环氧化吲哚是一种作为抗乳腺癌药物的小分子MDM2-p53相互作用抑制剂。化合物5b在携带MCF-7异种移植瘤的裸鼠中表现出显著的抗增殖活性。发现化合物5b通过调节野生型p53表达的乳腺癌细胞中的MDM2和p53表达来发挥作用。化合物5b刺激p53激活，引起调节细胞周期的下游效应物p21、pRb和细胞周期蛋白D1的调节。因此，该化合物引发G1-S期细胞周期停滞，这在经处理的乳腺癌细胞的流式细胞术分析中很明显。因此，化合物5b恢复了p53功能，这触发了与G1/S期细胞周期停滞一致的分子事件。
