Discovery of pyrrolospirooxindole derivatives as novel cyclin dependent kinase 4 (CDK4) inhibitors by catalyst-free, green approach

Ahmed Kamal; Rasala Mahesh; V Lakshma Nayak; Korrapati Suresh Babu; G Bharath Kumar; Anver Basha Shaik; Jeevak Sopanrao Kapure; Abdullah Alarifi

doi:10.1016/j.ejmech.2015.11.046

Discovery of pyrrolospirooxindole derivatives as novel cyclin dependent kinase 4 (CDK4) inhibitors by catalyst-free, green approach

Eur J Med Chem. 2016 Jan 27:108:476-485. doi: 10.1016/j.ejmech.2015.11.046. Epub 2015 Dec 2.

Authors

Ahmed Kamal¹, Rasala Mahesh², V Lakshma Nayak², Korrapati Suresh Babu², G Bharath Kumar², Anver Basha Shaik², Jeevak Sopanrao Kapure³, Abdullah Alarifi⁴

Affiliations

¹ Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Catalytic Chemistry Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
² Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
³ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
⁴ Catalytic Chemistry Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.

PMID: 26708114
DOI: 10.1016/j.ejmech.2015.11.046

Abstract

Aiming to develop a new target for the anticancer treatment, a series of 5'H-spiro[indoline-3,4'-pyrrolo [1,2-a]quinoxalin]-2-ones has been synthesized by simple, highly efficient and environmentally friendly method in excellent yields under catalyst-free conditions using ethanol as a green solvent. A simple filtration of the reaction mixture and subsequent drying affords analytically pure products. The synthesized derivatives were evaluated for their antiproliferative activity against five different human cancer cell lines, among the congeners compound 3n showed significant cytotoxicity against the human prostate cancer (DU-145). Flow cytometric analysis revealed that this compound induces cell cycle arrest in the G0/G1 phase and Western blot analysis suggested that reduction in Cdk4 expression level leads to apoptotic cell death. This was further confirmed by mitochondrial membrane potential ((ΔΨm), Annexin V-FITC assay and docking experiments. Furthermore, it was observed that there is an increase in expression levels of cyclin dependent kinase inhibitors like Cip1/p21 and Kip1/p27.

Keywords: Apoptosis; Cytotoxicity; Ethanol; Isatin; Spirooxindole.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Flow Cytometry
Green Chemistry Technology*
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinoxalines / chemical synthesis
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Structure-Activity Relationship

Substances

5'H-spiro(indoline-3,4'-(1,2-a)quinoxalin)-2-one
Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Quinoxalines
CDK4 protein, human
Cyclin-Dependent Kinase 4