Department of Chemistry , Lomonosov Moscow State University , Leninskie Gory 1-3 , Moscow 119991 , Russia.
Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences , Leninskiy pr. 31 , Moscow 119991 , Russia.
J Org Chem. 2019 Mar 15;84(6):3340-3356. doi: 10.1021/acs.joc.8b03208. Epub 2019 Feb 26.
A novel stereocontrolled assembly of spiro[oxindole-3,2'-pyrrolidines] via [3+2]-cycloaddition of donor-acceptor cyclopropanes to electron-poor ketimines, iminooxindoles, was developed. The method allows for efficient employment of common readily available donor-acceptor cyclopropanes, functionalized with ester, keto, nitro, cyano etc. groups, and N-unprotected iminooxindoles. The stereospecificity of the initial S2-like imine attack on a cyclopropane molecule together with a high diastereoselectivity of further C-C bond formation facilitate a rapid access to spiro[oxindole-3,2'-pyrrolidines] in their optically active forms. Preliminary in vitro testing of the synthesized compounds against LNCaP (p53+) and PC-3 (p53-) cells revealed good antiproliferative activities and p53-selectivity indices for several compounds that are intriguing in terms of their further investigation as inhibitors of MDM2-p53 interaction.
通过给电子缺电子酮亚胺、亚氨基氧化吲哚的亲双烯体环丙烷[3+2]-环加成，开发了一种新型的螺[氧吲哚-3,2'-吡咯烷]的立体控制组装。该方法可以有效地利用常见的易得的带有酯、酮、硝基、氰基等基团的供体-受体环丙烷，以及未保护的亚氨基氧化吲哚。初始 S2 型亚胺对环丙烷分子的立体特异性攻击，以及进一步 C-C 键形成的高非对映选择性，有利于快速获得其光学活性形式的螺[氧吲哚-3,2'-吡咯烷]。对合成化合物对 LNCaP（p53+）和 PC-3（p53-）细胞的初步体外测试表明，几种化合物具有良好的抗增殖活性和 p53 选择性指数，这对于进一步研究作为 MDM2-p53 相互作用抑制剂的化合物具有重要意义。
