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

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.