Synthesis and Evaluation of a New Generation of Orally Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors as Anticancer Agents

Abstract

Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.

Synthesis of novel 4-(1H-benzimidazol-2-yl)benzene-1,3-diols and their cytotoxic activity against human cancer cell lines

“…In addition, it was orally bioavailable and possessed good in vivo efficacy in a murine melanoma model (Penning et al, 2010). Other benzimidazole-4-carboxamide analogues as PARP-1 inhibitors with high cellular activity were also presented (Tong et al, 2009).…”

Recent advancements in oxadiazole-based anticancer agents

“…Tong et al described the synthesis of compound 55 showed the best activity with EC 50 value of 3.7 µM [22]. Oxadiazole compounds 56 and 57 were appeared as potent members of anticancer family of drugs [23].…”

Synthesis and biological evaluation of N-hydroxybenzimidazoles as potential anticancer agents targeting human lactate dehydrogenase A

“…As a bioisostere of indole, benzimidazole skeleton was incorporated into the target compounds. This is due to the fact that benzimidazoles have been frequently found to display a variety of biological activities such as anticancer [25] and antiproliferative properties [26]. Moreover, compared with the indole ring, the benzimidazole moiety more readily binds with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities.…”