TY - JOUR
TI - Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer
AU - Bantzi, M.
AU - Augsburger, F.
AU - Loup, J.
AU - Berset, Y.
AU - Vasilakaki, S.
AU - Myrianthopoulos, V.
AU - Mikros, E.
AU - Szabo, C.
AU - Bochet, C.G.
JO - Journal of Medicinal Chemistry
PY - 2021
VL - 64
TODO - 9
SP - 6221-6240
PB - American Chemical Society
SN - 0022-2623, 1520-4804
TODO - 10.1021/acs.jmedchem.1c00260
TODO - 3-mercaptopyruvate sulphurtransferase;  antineoplastic agent;  enzyme inhibitor;  pyrimidinone derivative;  sulfurtransferase, animal;  cell proliferation;  chemistry;  colon tumor;  dose response;  drug effect;  enzyme active site;  metabolism;  mouse;  pathology;  tumor cell line, Animals;  Antineoplastic Agents;  Catalytic Domain;  Cell Line, Tumor;  Cell Proliferation;  Colonic Neoplasms;  Dose-Response Relationship, Drug;  Enzyme Inhibitors;  Mice;  Pyrimidinones;  Sulfurtransferases
TODO - 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. © 2021 American Chemical Society.
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