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

[Display omitted] 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-2-aminoimidazole with functionalized quinolines and isoquinolines w...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 95; p. 117489
Main Authors:	Giri, Pritam, Batra, Pooja J., Kumari, Anuradha, Hura, Neha, Adhikary, Rishav, Acharya, Ayan, Guchhait, Sankar Kumar, Panda, Dulal
Format:	Journal Article
Language:	English
Published:	Elsevier Ltd 15-11-2023
Subjects:	Anticancer Clinical trial agent-inspired Colchicine-binding site Drug-likeness G2/M arrest Natural product-inspired NP-privileged motif Tubulin polymerization inhibition Natural product-inspired BSA NP-privileged motif Drug-likeness G2/M arrest Tubulin polymerization inhibition FBS PI Colchicine-binding site CA-4 Clinical trial agent-inspired Anticancer
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Summary:	[Display omitted] 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-2-aminoimidazole 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 µM. QTMP displayed higher aqueous stability than CA-4 at 37 °C. Further, in silico analysis of QTMP indicated excellent drug-like properties, including good aqueous solubility, balanced hydrophilicity-lipophilicity, and high GI-absorption ability. The results together suggest that QTMP has anticancer potential.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2023.117489