文摘
As a continuation of our efforts to discover and develop the apoptosis-inducing 4-aryl-4H-chromenes asnovel anticancer agents, we explored the SAR of fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl groupwas found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were foundto inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not changethe mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC50of 5 nM and a highly potent inhibitor of cell proliferation with a GI50 of 8 nM in T47D cells.
