Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer

  • J Med Chem. 2021 May 13;64(9):6221-6240. doi: 10.1021/acs.jmedchem.1c00260.
Marina Bantzi  1  2 ,  Fiona Augsburger  2 ,  Jérémie Loup  1 ,  Yan Berset  1 ,  Sofia Vasilakaki  3 ,  Vassilios Myrianthopoulos  3 ,  Emmanuel Mikros  3 ,  Csaba Szabo  2 ,  Christian G Bochet  1
Affiliations
  • 1. Department of Chemistry, University of Fribourg, 1700 Fribourg, Switzerland.
  • 2. Chair of Pharmacology, Faculty of Science and Medicine University of Fribourg, 1700 Fribourg, Switzerland.
  • 3. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, 15772 Athens, Greece.
PMID: 33856792 DOI: 10.1021/acs.jmedchem.1c00260
Abstract

The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H2S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H2S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon Cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (1b) was also confirmed on the growth of MC38 tumors in mice.

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