C3 酯侧链在 Maytansinoids 的抗肿瘤活性中起关键作用。,Biochemical and Biophysical Research Communications

当前位置： X-MOL 学术 › Biochem. Biophys. Res. Commun. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

C3 酯侧链在 Maytansinoids 的抗肿瘤活性中起关键作用。
Biochemical and Biophysical Research Communications ( IF 2.5 ) Pub Date : 2021-06-15 , DOI: 10.1016/j.bbrc.2021.05.071
Wenting Li ₁ , Minhao Huang ₂ , Yuyan Li ₁ , Anjie Xia ₁ , Lun Tan ₁ , Zhixiong Zhang ₁ , Yuxi Wang ₃ , Jinliang Yang ₁

Affiliation

Maytansinoids 是 Maytansine 的化学衍生物，通常用作抗体药物偶联物 (ADC) 中的有效细胞毒性有效载荷。构效关系研究已确定 C3 酯侧链是美登木素类抗肿瘤活性的关键元素。在具有 D 构型的 C3 位置带有甲基的美登木素生物碱对各种细胞系的细胞毒性比其相应的 L-差向异构体低约 100 至 400 倍。手性如何影响抗癌活性的详细机制仍然难以捉摸。在这项研究中，我们确定了与美登醇、L-DM1-SMe 和 D-DM1-SMe 复合的微管蛋白的高分辨率晶体结构。我们发现酯部分的羰基氧原子和 L-DM1-SMe C3 侧链的尾部硫甲基分别与 9 位羟基和苯环形成强分子内相互作用，固定生物活性构象并增强结合亲和力。此外，基于配体和基于结构的虚拟筛选方法用于筛选商业大环化合物库，并挑选出 15 个大环结构作为推定的新美登素位点抑制剂。我们的研究为合理发现下一代美登素位点抑制剂提供了一种可能的策略。基于配体和基于结构的虚拟筛选方法用于筛选商业大环化合物库，并挑选出 15 个大环结构作为推定的新美登素位点抑制剂。我们的研究为合理发现下一代美登素位点抑制剂提供了一种可能的策略。基于配体和基于结构的虚拟筛选方法用于筛选商业大环化合物库，并挑选出 15 个大环结构作为推定的新美登素位点抑制剂。我们的研究为合理发现下一代美登素位点抑制剂提供了一种可能的策略。

"点击查看英文标题和摘要"

C3 ester side chain plays a pivotal role in the antitumor activity of Maytansinoids.

Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors.

更新日期：2021-06-15

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南