Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3‑Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity

Poly­(adenosine 5′-diphosphate-ribose)
polymerase (PARP)
inhibitors are a class of anticancer drugs that block the catalytic
activity of PARP proteins. Optimization of our lead compound 1 ((Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide;
PARP-1 IC50 = 434 nM) led to a tetrazolyl analogue (51, IC50 = 35 nM) with improved inhibition. Isosteric
replacement of the tetrazole ring with a carboxyl group (60, IC50 = 68 nM) gave a promising new lead, which was subsequently
optimized to obtain analogues with potent PARP-1 IC50 values
(4–197 nM). PARP enzyme profiling revealed that the majority
of compounds are selective toward PARP-2 with IC50 values
comparable to clinical inhibitors. X-ray crystal structures of the
key inhibitors bound to PARP-1 illustrated the mode of interaction
with analogue appendages extending toward the PARP-1 adenosine-binding
pocket. Compound 81, an isoform-selective PARP-1/-2 (IC50 = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic
effect toward breast cancer gene 1 (BRCA1)-deficient
cells compared to isogenic BRCA1-proficient cells.