Discovery and Structure–Activity Relationship of Novel 23-Dihydrobenzofuran-7-carboxamideand 23-Dihydrobenzofuran-3(2H)-one-7-carboxamideDerivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

摘要

Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound >3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (>36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene >58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds >66–>68, >70, >72, and >73; IC50 values from 0.718 to 0.079 μM). Compound >66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (>−)>-13c, >59, and >65) bound toa multidomain PARP-1 structure were obtained, providing insights intofurther development of these inhibitors.