Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

No abstract

in Wiley Online Library (wileyonlinelibrary.com).In an extension of our prior work with indoles and pyrroles, the Diels-Alder chemistry of substituted 2vinylthiophenes was explored, using N-phenylmaleimide as the dienophile. The dienes were prepared from thiophene in two steps by addition to various ketones, followed by dehydration (40-60% overall yields). Although most dienes were obtained as regioisomeric mixtures, the Diels-Alder-derived products were easily purified by chromatography. The main cycloaddition pathway was endo Diels-Alder addition followed by exo ene addition of a second molecule of dienophile (19-33% yields). Several products were desulfurized with Raney nickel (48-62% yields). Unfortunately, no thiophene-derived products showed the promising biological activity of the previously reported indole analogs.

In the title solvated crystal, C8H5Br2NO3·C3H8O, the acid molecules form inversion dimers by pairwise N—H...O hydrogen bonds between carbamoyl groups and the carboxyl and carbamoyl groups link to form head-to-tail inversion dimers. The 2-propanol hydroxyl group interposes between adjacent head-tail pairs, resulting in C 3 3(10) chains of hydrogen bonds propagating along [100]. The molecules of 2-propanol are disordered over two sets of sites in a 0.598 (8):0.402 (8) ratio. The best-fit planes of the carbamoyl group and benzene ring are inclined by 88.26 (11)°. This is a greater inclination than was previously reported with CH3, Cl, F or H in place of the Br atoms, although those analogues did not have a para carboxyl group.