Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

作者：Patel Maulik R; Bhatt Aaditya; Steffen Jamin D; Chergui Adel; Murai Junko; Pommier Yves; Pascal John M; Trombetta Louis D; Fronczek Frank R; Talele Tanaji T^*

来源：Journal of Medicinal Chemistry, 2014, 57(13): 5579-5601.

DOI：10.1021/jm5002502

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 mu M). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 mu M). 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%26apos;,4%26apos;-dihydroxybenzylidene 58 (IC50 = 0.531 mu M) showing a 30-fold improvement in potency. Various heterocycles attached at the 4%26apos;-hydroxyl/4%26apos;-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 mu M). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.

• 出版日期2014-7-10