Kemnitzer William, Kuemmerle Jared, Jiang Songchun, Sirisoma Nilantha, Kasibhatla Shailaja, Crogan-Grundy Candace, Tseng Ben, Drewe John, Cai Sui Xiong
EpiCept Corporation, Inc. 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3481-4. doi: 10.1016/j.bmcl.2009.05.012. Epub 2009 May 8.
As a continuation of our efforts to discover and develop the apoptosis inducing 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines as potential anticancer agents, we explored substitutions at the 4-, 5-, 6-, 7- and 8-positions of pyrrolo[1,2-a]quinoline. SAR studies showed that substitution at the 6-position by a small group such as Cl resulted in potent compounds. Substitutions at the 5- and 8-positions were tolerated while substitutions at the 4- and 7-position led to inactive compounds. Several compounds, including 2c, 3a, 3b and 3f, were found to be highly active against human breast cancer cells T47D with EC(50) values of 0.053-0.080microM, but much less active against human colon cancer cells HCT116 and hepatocellular carcinoma cancer cells SNU398 in the caspase activation assay. Compound 3f also was found to be highly active with a GI(50) value of 0.018microM against T47D cells in a growth inhibition assay.
作为我们发现和开发可诱导细胞凋亡的1-苯甲酰基-3-氰基吡咯并[1,2-a]喹啉作为潜在抗癌药物的努力的延续，我们探索了吡咯并[1,2-a]喹啉4、5、6、7和8位的取代情况。构效关系研究表明，用诸如Cl等小基团在6位进行取代会产生强效化合物。5位和8位的取代是可耐受的，而4位和7位的取代则导致化合物无活性。发现包括2c、3a、3b和3f在内的几种化合物对人乳腺癌细胞T47D具有高活性，其半数有效浓度（EC(50)）值为0.053 - 0.080微摩尔，但在半胱天冬酶激活试验中对人结肠癌细胞HCT116和肝癌细胞SNU398的活性要低得多。在生长抑制试验中，还发现化合物3f对T47D细胞具有高活性，其半数生长抑制浓度（GI(50)）值为0.018微摩尔。
