Kemnitzer William, Kasibhatla Shailaja, Jiang Songchun, Zhang Hong, Zhao Jianghong, Jia Shaojuan, Xu Lifen, Crogan-Grundy Candace, Denis Réal, Barriault Nancy, Vaillancourt Louis, Charron Sylvie, Dodd Jennifer, Attardo Giorgio, Labrecque Denis, Lamothe Serge, Gourdeau Henriette, Tseng Ben, Drewe John, Cai Sui Xiong
Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2005 Nov 1;15(21):4745-51. doi: 10.1016/j.bmcl.2005.07.066.
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 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at the 7-position. Di-substitution at either the 5,7-positions or the 6,7-positions generally led to a large decrease in potency. Di-substitution at the 7,8-positions, in general, was found to result in potent compounds. 7-NMe2, 7-NHEt, 7-OMe, and 7,8-di-NH2 analogs were found to have similar SAR for the 4-aryl group, and several 7-substituted and 7,8-di-substituted analogs were found to have similar potencies as the lead compound MX58151 (2a) both as caspase activators and inhibitors of cell proliferation.
作为我们发现和开发可诱导细胞凋亡的4-芳基-4H-色烯作为新型抗癌药物的努力的延续，我们探索了在7-以及5-、6-、8-位进行修饰的4-芳基-4H-色烯的构效关系。结果发现，在7-位优选一个小的疏水基团，如NMe2、NH2、NHEt和OMe。在5,7-位或6,7-位的双取代通常会导致活性大幅下降。一般来说，在7,8-位的双取代会产生活性化合物。发现7-NMe2、7-NHEt、7-OMe和7,8-二-NH2类似物对于4-芳基具有相似的构效关系，并且发现几种7-取代和7,8-双取代类似物作为半胱天冬酶激活剂和细胞增殖抑制剂与先导化合物MX58151（2a）具有相似的活性。
