1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: anti-cancer agents that target nucleophosmin 1 (NPM1)

摘要

In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolyl methylene barbituric acid analogues (>7a–7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogues (>7i–7l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogues >7i, >7j, and >7k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values < 2 μM. Compound >7k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22–0.35 μM. Analogue >7i also exhibited GI50 values < 0.35 μM against three of the leukemia cell lines in the sub-panel. Analogues >7i, >7j, >7k and >7l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds >7k and >7l were found to cause dose-dependent apoptosis (AP50 =1.75 μM and 3.3 μM respectively). Compound >7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: i.e. A498 renal cancer (GI 50 = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI50 = 0.22 μM), melanoma MDA-MB-435 (GI50 = 0.22 μM), and breast cancer HS 578T (GI50 = 0.22 μM) cell lines. Molecular docking studies suggest that compounds >7k and >7l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors >7i, >7j, >7k, and >7l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. 2009 Elsevier Ltd. All rights reserved.