Exploring the newer oxadiazoles as real inhibitors of human SIRT2 in hepatocellular cancer cells

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127330. doi: 10.1016/j.bmcl.2020.127330.

Dukanya ¹, Muthu K Shanmugam ², Shobith Rangappa ³, Prashant K Metri ¹, Surender Mohan ¹, Basappa ⁴, Kanchugarakoppal S Rangappa ⁵

Affiliations

1 Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
3 Adichunchanagiri Institute for Molecular Medicine, BG Nagara-571448, NagamangalaTaluk, Mandya District, India.
4 Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: salundibasappa@gmail.com.
5 Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

PMID: 32631535 DOI: 10.1016/j.bmcl.2020.127330

Abstract

A novel series of indazole tethered oxadiazoles (OTDs) derivatives were synthesized, characterized and screened for their anti-proliferative activity against hepatocellular carcinoma (HCC) cells. OTDs structure was further confirmed by Single-crystal X-ray diffraction studies. Among the tested OTDs, compound 2-(4-methoxyphenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole was found to inhibit the catalytical activity of SIRT2 and brings about Apoptosis as shown by western blot analysis and flow cytometry data. Also, the tested OTDs were found to interact with the active site of human SIRT2 in silico but not with the cavity of co-crystal ligand 5-(3- hydroxypropyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole, which indicate that these OTDs has potential in the development of SIRT2 inhibitors in liver Cancer models.

Keywords

Drug-discovery; HCC; Indazole; Oxadiazole; SIRT2.

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