Design, Synthesis and Evaluation of AdSS Bisubstrate Inhibitors

Nidhi Tibrewal; Gregory I Elliott

doi:10.1002/cmdc.202000498

Design, Synthesis and Evaluation of AdSS Bisubstrate Inhibitors

ChemMedChem. 2020 Dec 3;15(23):2269-2272. doi: 10.1002/cmdc.202000498. Epub 2020 Sep 10.

Authors

Nidhi Tibrewal¹, Gregory I Elliott^{1

2

3}

Affiliations

¹ Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536-0596, USA.
² Department of Chemistry, University of Kentucky, Lexington, KY 40536-0596, USA.
³ Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92181-1030, USA.

PMID: 32779344
DOI: 10.1002/cmdc.202000498

Abstract

Many cancers lack the expression of methylthioadenosine phosphorylase (MTAP). These cancers require adenylosuccinate synthetase (AdSS) for nucleic acid synthesis. By inhibiting adenylosuccinate synthetase, we potentially have a new therapeutic agent. Bisubstrate inhibitors were synthesized and evaluated against purified AdSS. The best activity was obtained with adenosine bearing a four-carbon linker that connects the N-formyl-N-hydroxy moiety to the 6-position of the purine nucleoside.

Keywords: adenylosuccinate synthetase; lung cancer; methylthioadenosine phosphorylase; small molecules.

Publication types

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

MeSH terms

Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Purine Nucleosides / chemical synthesis
Purine Nucleosides / chemistry
Purine Nucleosides / pharmacology*
Purine-Nucleoside Phosphorylase

Substances

Enzyme Inhibitors
Purine Nucleosides
Purine-Nucleoside Phosphorylase
5'-methylthioadenosine phosphorylase