Discovery of Novel Bromophenol–Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase‑1 (PARP-1) for Use in Cancer

Poly­(ADP-ribose)
polymerase-1 (PARP-1) is a new potential target
for anticancer drug discovery. A series of bromophenol–thiosemicarbazone
hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated
for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity
(IC50 = 29.5 nM) over PARP-2 (IC50 > 1000
nM)
and potent anticancer activities toward the SK-OV-3, Bel-7402 and
HepG2 cancer cell lines (IC50 = 2.39, 5.45, and 4.60 μM),
along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft
model. Further study demonstrated that compound 11 played
an antitumor role through multiple anticancer mechanisms, including
the induction of apoptosis and cell cycle arrest, cellular accumulation
of DNA double-strand breaks, DNA repair alterations, inhibition of
H2O2-triggered PARylation, antiproliferative
effects via the production of cytotoxic reactive oxygen species, and
autophagy. In addition, compound 11 displayed good pharmacokinetic
characteristics and favorable safety. These observations demonstrate
that compound 11 may serve as a lead compound for the
discovery of new anticancer drugs.