Development of QTMP: A promising anticancer agent through NP-Privileged Motif-Driven structural modulation

In this study of creating new molecules from clinical trial agents, an approach of Combretastatin structural modulation with the installation of NP-privileged motifs was considered, and a series of trimethoxyphenyl-2aminoimidazole with functionalized quinolines and isoquinolines was investigated. An exciting method of quinoline C3-H iodination coupled with imidazopyridine-C3-H arylation and hydrazine-mediated fused-ring cleavage enabled synthesizing a class of compounds with two specific unsymmetric aryl substitutions. Interestingly, three compounds (6, 11, and 13) strongly inhibited HeLa cell proliferation with a half-maximal inhibitory concentration (10-46 nM). Among the compounds, compound 6 (QTMP) showed stronger antiproliferative ability than CA-4 (a clinical trial agent) in various cancer cell lines, including cervical, lung, breast, highly metastatic breast, and melanoma cells. QTMP inhibited the assembly of purified tubulin, depolymerized microtubules of A549 lung carcinoma cells, produced defective spindles, and arrested the cells in the G2/M phase. Further, QTMP binds to the colchicine site in tubulin with a dissociation constant of 5.0 +/- 0.6 mu M. QTMP displayed higher aqueous stability than CA-4 at 37 degrees C. Further, in silico analysis of QTMP indicated excellent drug-like properties, including good aqueous solubility, balanced hydrophilicity-lipophilicity, and high GIabsorption ability. The results together suggest that QTMP has anticancer potential.

Automated summary

This study explored the creation of new molecules with anticancer potential from clinical trial agents. A compound named QTMP showed stronger antiproliferative ability than the clinical trial agent CA-4 in various cancer cell lines, and it also affected microtubule assembly and cell cycle progression. In vitro analysis indicated that QTMP possesses favorable drug-like properties.