Structure-Based Design and Synthesis of N-Substituted 3-Amino-β-Carboline Derivatives as Potent αβ-Tubulin Degradation Agents

作者：Yong Li, Yan Liu, Zejiang Zhu, Wei Yan, Chufeng Zhang, Zhuang Yang, Peng Bai, Minghai Tang, Mingsong Shi, Wen He, Suhong Fu, Jiang Liu, Kai Han, Li Jiewen, Lixin Xie, Haoyu Ye, Jianhong Yang, Lijuan Chen · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.1c02159 · 被引用次数：29 · 研究领域：Synthesis and bioactivity of alkaloids、Cancer therapeutics and mechanisms、Cancer Mechanisms and Therapy

So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting αβ-tubulin degradation. To further improve its antiproliferative activity, 66 derivatives or analogues of 2 were designed and synthesized based on 2 -tubulin cocrystal structure. Among them, 12b displayed nanomolar potency against a variety of tumor cells, including paclitaxel- and adriamycin-resistant cell lines. 12b binds to the colchicine site and promotes αβ-tubulin degradation in a concentration-dependent manner via the ubiquitin–proteasome pathway. The X-ray crystal structure revealed that 12b binds in a similar manner as 2, but there is a slight conformation change of the B ring, which resulted in better interaction of 12b with surrounding residues. 12b effectively suppressed tumor growth at an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive) and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective TGIs of 92.42 and 79.75% without obvious side effects, supporting its potential utility as a tumor-therapeutic compound.