Synthesis of 1,4-dihydropyrazolo[4,3-b]indoles via intramolecular C(sp2)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment

Manpreet Kaur; Vikrant Mehta; Aabid Abdullah Wani; Sahil Arora; Prasad V Bharatam; Ashoke Sharon; Sandeep Singh; Raj Kumar

doi:10.1016/j.bioorg.2021.105114

Synthesis of 1,4-dihydropyrazolo[4,3-b]indoles via intramolecular C(sp²)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment

Bioorg Chem. 2021 Sep:114:105114. doi: 10.1016/j.bioorg.2021.105114. Epub 2021 Jun 29.

Authors

Manpreet Kaur¹, Vikrant Mehta², Aabid Abdullah Wani³, Sahil Arora¹, Prasad V Bharatam³, Ashoke Sharon⁴, Sandeep Singh⁵, Raj Kumar⁶

Affiliations

¹ Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda-151401, Punjab, India.
² Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda-151401, Punjab, India.
³ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), SAS. Nagar, India.
⁴ Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
⁵ Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda-151401, Punjab, India. Electronic address: sandeepsingh82@cup.edu.in.
⁶ Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda-151401, Punjab, India. Electronic address: raj.khunger@gmail.com.

PMID: 34243073
DOI: 10.1016/j.bioorg.2021.105114

Abstract

We herein report a new synthetic route for a series of unreported 1,4-dihydropyrazolo[4,3-b]indoles (6-8) via deoxygenation of o-nitrophenyl-substituted N-aryl pyrazoles and subsequent intramolecular (sp²)-N bond formation under microwave irradiation expedite modified Cadogan condition. This method allows access to NH-free as well as N-substituted fused indoles. DFT study and controlled experiments highlighted the role of nitrene insertion as one of the plausible reaction mechanisms. Furthermore, the target compounds exhibited cytotoxicity at low micromolar concentration against lung (A549), colon (HCT-116), and breast (MDA-MB-231, and MCF-7) cancer cell lines, induced the ROS generation and altered the mitochondrial membrane potential of highly aggressive MDA-MB-231 cells. Further investigations revealed that these compounds were selective Topo I (6h) or Topo II (7a, 7b) inhibitors.

Keywords: 1,4-Dihydropyrazolo[4,3-b]indoles; CN bond formation; Cadogan Cyclization; Cancer; DFT study; Topoisomerase inhibitors.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Density Functional Theory*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Imines / chemistry
Imines / pharmacology*
Membrane Potential, Mitochondrial / drug effects
Molecular Docking Simulation
Molecular Structure
Reactive Oxygen Species / analysis
Reactive Oxygen Species / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Imines
Reactive Oxygen Species
phenylnitrene