Structural simplification of bioactive natural products with multicomponent synthesis. 3. Fused uracil-containing heterocycles as novel topoisomerase-targeting agents.

摘要: After the initial discovery of antiproliferative and apoptosis-inducing properties a camptothecin-inspired pentacycle based on 1H-indeno[2′,1′:5,6]dihydropyrido[2,3-d]pyrimidine scaffold, library its analogues as well their oxidized planar counterparts were prepared utilizing practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar potencies toward panel human cancer cell lines. Biochemical experiments are consistent with dihydropyridine members undergoing intracellular oxidation corresponding pyridines, which then inhibit topoisomerase II activity, leading inhibition proliferation death. Because facile preparation promising antitopoisomerase both pyridine-based represent convenient starting point for anticancer drug discovery.