Organotin benzohydroxamate derivatives (OTBH) target colchicine-binding site exerting potent antitumor activity both in vitro and vivo revealed by quantitative proteomic analysis

Abstract

The activity of four typical organotin benzohydroxamate compounds (OTBH) with the different electronegativity of fluorine and chlorine atoms was assessed both in vitro and in vivo, revealing that they all exhibited notable antitumor effects. Furthermore, it was discovered that the biochemical capacity against cancer was influenced by their substituents' electronegativity and structural symmetry. For instance, benzohydroxamate derivatives with single chlorine at the fourth site on the benzene ring, two normal‑butyl organic ligands, a symmetrical structure, and so on ([n-Bu2Sn[{4-ClC6H4C(O)NHO}2] (OTBH-1)) had stronger antitumor activity than others. Furthermore, the quantitative proteomic analysis discovered 203 proteins in HepG2 cells and 146 proteins in rat liver tissues that were differently identified before and after administration. Simultaneously, bioinformatics analysis of differentially expressed proteins demonstrated that the antiproliferative effects involved in the microtubule-based process, tight junction and its downstream apoptosis pathways. As predicted analytically, molecular docking indicated that ''-O-'' were the target docking atoms for the colchicine-binding site; meanwhile, this site was additionally verified by the EBI competition experiment and the microtubule assembly inhibition test. In conclusion, these derivatives promising for developing microtubule-targeting agents (MTAs) were shown to target the colchicine-binding site, impair cancer cell microtubule networks, and then halt mitosis and trigger apoptosis.