4-Flourophenyl-substituted 5H-indeno[1,2-b]pyridinols with enhanced topoisomerase IIα inhibitory activity: Synthesis, biological evaluation, and structure-activity relationships.

Abstract

A series of fluorinated and hydroxylated 2,4-diphenyl indenopyridinols were designed and synthesized using l-proline-catalyzed and microwave-assisted synthetic methods for the development of new anticancer agents. Adriamycin and etoposide were used as reference compounds for the evaluation of topo IIα inhibitory and anti-proliferative activity of the synthesized compounds. Exploring the structure-activity relationships of 36 prepared compounds and biological results, most of the compounds with ortho- and para-fluorophenyl at 4-position of indenopyridinol ring displayed strong topo IIα inhibition. In addition, the majority of the ortho- and meta-fluorophenyl substituted compounds 1-24 displayed strong anti-proliferative activity against DU145 prostate cancer cell line compared to the positive controls. Interestingly, compound 4 possessing ortho-phenolic and ortho-fluorophenyl group at 2- and 4-position, respectively of the central pyridine ring showed high anti-proliferative activity (IC50 = 0.82 μM) against T47D human breast cancer cell line, while para-phenolic and para-fluorophenyl substituted compound 36 exhibited potent topo IIα inhibitory activity with 94.7% and 88.6% inhibition at 100 μM and 20 μM concentration, respectively. A systematic comparison between the results of this study and the previous study indicated that minor changes in the position of functional groups in the structure affect the topo IIα inhibitory activity and anti-proliferative activity of the compounds. The findings from this study will provide valuable information to the researchers working on the medicinal chemistry of topoisomerase IIα-targeted anticancer agents.

• Authors: Surendra Kunwar, Soo-Yeon Hwang, Pramila Katila, Minjung Seo, Tara Man Kadayat, Youngjoo Kwon, Eung-Seok Lee
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 116 Pg. 105349 (11 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34536927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Indenes
• Poly-ADP-Ribose Binding Proteins
• Pyridines
• Topoisomerase II Inhibitors
• indene
• DNA Topoisomerases, Type II
• TOP2A protein, human
• pyridine

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type II (metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Indenes (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Poly-ADP-Ribose Binding Proteins (antagonists & inhibitors, metabolism)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Topoisomerase II Inhibitors (chemical synthesis, chemistry, pharmacology)