title: Synthesis and activity of benzimidazole-1,3-dioxide inhibitors of separase.
abstract: Due to the oncogenic activity of cohesin protease, separase in human cancer cells, modulation of separase enzymatic activity could constitute a new therapeutic strategy for targeting resistant, separase-overexpressing aneuploid tumors. Herein, we report the synthesis, structural information, and structure-activity relationship (SAR) of separase inhibitors based on modification of the lead molecule 2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide, named Sepin-1, (1) identified from a high-throughput-screen. Replacement of -NO2 at C5 with other functional groups reduce the inhibitory activity in separase enzymatic assay. Substitution of the two methyl groups with other alkyl chains at the C2 moderately improves the effects on the inhibitory activity of those compounds. Modifications on 2H-benzimidazole-1,3-dioxide or the skeleton have variable effect on inhibition of separase enzymatic activity. Density-functional theory (DFT) calculations suggest there may be a correlation between the charges on the oxide moieties on these compounds and their activity in inhibiting separase enzyme.
authors.affiliation: Department of Chemistry, University of Houston, Houston, TX 77204, United States.
authors.forename: Ha T
authors.initials: HT
authors.lastname: Do
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
authors.forename: Nenggang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: pati@bcm.edu.
authors.forename: Debananda
authors.initials: D
authors.lastname: Pati
authors.affiliation: Department of Chemistry, University of Houston, Houston, TX 77204, United States. Electronic address: srgilbe2@central.uh.edu.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gilbertson
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D064247:Separase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D064247:Separase
keywords: Benzimidazole; Breast cancer; Inhibitor; Separase