Kemnitzer William, Drewe John, Jiang Songchun, Zhang Hong, Zhao Jianghong, Crogan-Grundy Candace, Xu Lifen, Lamothe Serge, Gourdeau Henriette, Denis Réal, Tseng Ben, Kasibhatla Shailaja, Cai Sui Xiong
Epicept Corporation, 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
J Med Chem. 2007 Jun 14;50(12):2858-64. doi: 10.1021/jm070216c. Epub 2007 May 11.
As a continuation of our efforts to discover and develop the apoptosis-inducing 4-aryl-4H-chromenes as novel 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 group was found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were found to inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not change the mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC50 of 5 nM and a highly potent inhibitor of cell proliferation with a GI50 of 8 nM in T47D cells.
作为我们发现和开发具有诱导细胞凋亡作用的4-芳基-4H-色烯作为新型抗癌药物的努力的延续，我们探索了7,8位稠环的构效关系。结果发现，五元芳环，如7位或9位含氮的吡咯环，是较为理想的。六元芳环，如苯并环或吡啶环，也能产生强效化合物。对于7,8位带有稠环的色烯，发现4-芳基的构效关系相似。这些化合物被发现能抑制微管蛋白聚合，这表明7,8位环化形成环并不改变其作用机制。化合物2h被鉴定为一种高效的细胞凋亡诱导剂，在T47D细胞中的EC50为5 nM，同时也是一种高效的细胞增殖抑制剂，GI50为8 nM。
