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

Pritam Giri; Pooja J Batra; Anuradha Kumari; Neha Hura; Rishav Adhikary; Ayan Acharya; Sankar Kumar Guchhait; Dulal Panda

doi:10.1016/j.bmc.2023.117489

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

Bioorg Med Chem. 2023 Nov 15:95:117489. doi: 10.1016/j.bmc.2023.117489. Epub 2023 Oct 5.

Authors

Pritam Giri¹, Pooja J Batra², Anuradha Kumari², Neha Hura¹, Rishav Adhikary², Ayan Acharya¹, Sankar Kumar Guchhait³, Dulal Panda⁴

Affiliations

¹ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
² Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India.
³ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India. Electronic address: skguchhait@niper.ac.in.
⁴ Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India; National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab, 160062, India. Electronic address: panda@iitb.ac.in.

PMID: 37816266
DOI: 10.1016/j.bmc.2023.117489

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00003768 NCT00960557 NCT00060242 NCT01423149 NCT00507429.

Keywords: Anticancer; Clinical trial agent-inspired; Colchicine-binding site; Drug-likeness; G2/M arrest; NP-privileged motif; Natural product-inspired; Tubulin polymerization inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Molecular Structure
Structure-Activity Relationship
Tubulin Modulators / pharmacology
Tubulin* / metabolism

Substances

Tubulin
Tubulin Modulators
Antineoplastic Agents

Associated data

ClinicalTrials.gov/NCT00003768
ClinicalTrials.gov/NCT00960557
ClinicalTrials.gov/NCT00060242
ClinicalTrials.gov/NCT01423149
ClinicalTrials.gov/NCT00507429