Τίτλος:
Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Bantzi, M.
Augsburger, F.
Loup, J.
Berset, Y.
Vasilakaki, S.
Myrianthopoulos, V.
Mikros, E.
Szabo, C.
Bochet, C.G.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
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
DOI:
10.1021/acs.jmedchem.1c00260
