Synthesis, biological evaluation and in silico and in vitro mode-of-action analysis of novel dihydropyrimidones targeting PPAR-γ

Hanumantharayappa Bharathkumar; Shardul Paricharak; K. R. Dinesh; Kodappully Sivaraman Siveen; Julian E. Fuchs; Shobith Rangappa; C. D. Mohan; Nima Mohandas; Alan Prem Kumar; Gautam Sethi; Andreas Bender; Basappa; K. S. Rangappa

doi:10.1039/C4RA08713E

Synthesis, biological evaluation and in silico and in vitro mode-of-action analysis of novel dihydropyrimidones targeting PPAR-γ†

Hanumantharayappa Bharathkumar,^a Shardul Paricharak,^bc K. R. Dinesh,^a Kodappully Sivaraman Siveen,^d Julian E. Fuchs,^b Shobith Rangappa,^ef C. D. Mohan,^g Nima Mohandas,^d Alan Prem Kumar,^dfhi Gautam Sethi,^d Andreas Bender,*^b Basappa*^a and K. S. Rangappa*^g

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* Corresponding authors

^a Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India
E-mail: salundibasappa@gmail.com

^b Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK

^c Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands

^d Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

^e Interdisciplinary Research Group of Infectious Diseases, Singapore-MIT Alliance for Research & Technology Centre (SMART), Singapore

^f Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore

^g Department of Chemistry, University of Mysore, Manasagangotri, Mysore 560001, India

^h School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia, Australia

ⁱ Department of Biological Sciences, University of North Texas, Denton, Texas, USA

Abstract

Hepatocellular carcinoma, a fatal liver cancer, affects 600 000 people annually and ranks third in cancer-related lethality. In this work we report the synthesis and related biological activity of novel dihydropyrimidones. Among the tested compounds, 5-acetyl-4-(1H-indol-3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4g) was found to be most active towards the HepG2 cell line (IC₅₀ = 17.9 μM), being at the same time 7.6-fold selective over normal (LO2) liver cells (IC₅₀ = 136.9 μM). Subsequently, we identified peroxisome proliferator-activated receptor γ as a target of compound 4g using an in silico approach, and confirmed this mode-of-action experimentally.

RSC Advances

Synthesis, biological evaluation and in silico and in vitro mode-of-action analysis of novel dihydropyrimidones targeting PPAR-γ†

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