Nano-Zirconium Dioxide Catalyzed Multicomponent Synthesis of Bioactive Pyranopyrazoles That Target Cyclin Dependent Kinase 1 in Human Breast Cancer Cells
Basappa Basappa,
Lisha K. Poonacha,
Zhang Xi,
Divakar Vishwanath,
Ji-Rui Yang,
Omantheswara Nagaraja,
Ananda Swamynayaka,
Mahendra Madegowda,
Arunachalam Chinnathambi,
Sulaiman Ali Alharbi,
Doddahosuru Mahadevappa Gurudatt,
Vijay Pandey,
Nanjundaswamy Shivananju,
Kwang Seok Ahn,
Gautam Sethi,
Peter E. Lobie,
Priya Babu Shubha
Affiliations
Basappa Basappa
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Lisha K. Poonacha
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Zhang Xi
Shenzhen Bay Laboratory, Shenzhen 518107, China
Divakar Vishwanath
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Ji-Rui Yang
Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Beijing 100084, China
Omantheswara Nagaraja
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India
Ananda Swamynayaka
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India
Mahendra Madegowda
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India
Arunachalam Chinnathambi
Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Sulaiman Ali Alharbi
Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Doddahosuru Mahadevappa Gurudatt
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Vijay Pandey
Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Beijing 100084, China
Nanjundaswamy Shivananju
Department of Biotechnology, Sri Jayachamarajendra College of Engineering, JSS, Technical Institutions Campus, Mysore 570006, India
Kwang Seok Ahn
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 24 Kyungheedaero, Dongdaemun-gu, Seoul 02447, Republic of Korea
Gautam Sethi
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
Peter E. Lobie
Shenzhen Bay Laboratory, Shenzhen 518107, China
Priya Babu Shubha
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Small molecules are being used to inhibit cyclin dependent kinase (CDK) enzymes in cancer treatment. There is evidence that CDK is a drug-target for cancer therapy across many tumor types because it catalyzes the transfer of the terminal phosphate of ATP to a protein that acts as a substrate. Herein, the identification of pyranopyrazoles that were CDK inhibitors was attempted, whose synthesis was catalyzed by nano-zirconium dioxide via multicomponent reaction. Additionally, we performed an in-situ analysis of the intermediates of multicomponent reactions, for the first-time, which revealed that nano-zirconium dioxide stimulated the reaction, as estimated by Gibbs free energy calculations of spontaneity. Functionally, the novel pyranopyrazoles were tested for a loss of cell viability using human breast cancer cells (MCF-7). It was observed that compounds 5b and 5f effectively produced loss of viability of MCF-7 cells with IC50 values of 17.83 and 23.79 µM, respectively. In vitro and in silico mode-of-action studies showed that pyranopyrazoles target CDK1 in human breast cancer cells, with lead compounds 5b and 5f having potent IC50 values of 960 nM and 7.16 μM, respectively. Hence, the newly synthesized bioactive pyranopyrazoles could serve as better structures to develop CDK1 inhibitors against human breast cancer cells.
