Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines

Umesh Prasad Yadav; Arshad J Ansari; Sahil Arora; Gaurav Joshi; Tashvinder Singh; Harsimrat Kaur; Nilambra Dogra; Raj Kumar; Santosh Kumar; Devesh M Sawant; Sandeep Singh

doi:10.1016/j.bioorg.2021.105464

Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines

Bioorg Chem. 2022 Jan:118:105464. doi: 10.1016/j.bioorg.2021.105464. Epub 2021 Nov 1.

Authors

Affiliations

¹ Department of Human Genetics and Molecular Medicine, School of Health Sciences Central University of Punjab, Bathinda 151401, India; Department of Biochemistry, All India Institute of Medical Sciences, Patna, India.
² Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Ajmer 305817, India.
³ Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda 151401, India.
⁴ Department of Human Genetics and Molecular Medicine, School of Health Sciences Central University of Punjab, Bathinda 151401, India.
⁵ Centre for Systems Biology & Bioinformatics, Panjab University, Chandigarh 160014, India.
⁶ Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda 151401, India. Electronic address: raj.khunger@cup.edu.in.
⁷ Department of Biochemistry, All India Institute of Medical Sciences, Patna, India. Electronic address: santoshnccs@gmail.com.
⁸ Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Ajmer 305817, India. Electronic address: dms@curaj.ac.in.
⁹ Department of Human Genetics and Molecular Medicine, School of Health Sciences Central University of Punjab, Bathinda 151401, India. Electronic address: sandeepsingh82@cup.edu.in.

PMID: 34785441
DOI: 10.1016/j.bioorg.2021.105464

Abstract

A series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC₅₀ values ranging from 1 to 5.5 μM. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase IIα inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression.

Keywords: 2-Arylimidazo[1,2-a]pyridinyl-3-amines; Anticancer; Topoisomerase inhibitors; Western blotting; p53.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Structure
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Pyridines