Discovery of N-methyl-4-(4-methoxyanilino)quinazolines as potent apoptosis inducers. Structure–activity relationship of the quinazoline ring |
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Authors: | Nilantha Sirisoma Azra Pervin Hong Zhang Songchun Jiang J Adam Willardsen Mark B Anderson Gary Mather Christopher M Pleiman Shailaja Kasibhatla Ben Tseng John Drewe Sui Xiong Cai |
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Institution: | 1. EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA;2. Myriad Pharmaceuticals Inc., 320 Wakara Way, Salt Lake City, UT 84108, USA |
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Abstract: | As a continuation of our efforts to discover and develop apoptosis inducing N-methyl-4-(4-methoxyanilino)quinazolines as novel anticancer agents, we explored substitution at the 5-, 6-, 7-positions of the quinazoline and replacement of the quinazoline by other nitrogen-containing heterocycles. A small group at the 5-position was found to be well tolerated. At the 6-position a small group like an amino was preferred. Substitution at the 7-position was tolerated much less than at the 6-position. Replacing the carbon at the 8-position or both the 5- and 8-positions with nitrogen led to about 10-fold reductions in potency. Replacement of the quinazoline ring with a quinoline, a benzod]1,2,3]triazine, or an isoquinoline ring showed that the nitrogen at the 1-position is important for activity, while the carbon at the 2-position can be replaced by a nitrogen and the nitrogen at the 3-position can be replaced by a carbon. Through the SAR study, several 5- or 6-substituted analogs, such as 2a and 2c, were found to have potencies approaching that of lead compound N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1g, EP128495, MPC-6827, Azixa®). |
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