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

Abstract In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs ( 7a – 7h ) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs ( 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 analogs 7i , 7j , and 7k demonstrated potent growth inhibitory effects in various cancer cell types with GI 50 values 7k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI 50 values in the range 0.22–0.35 μM. Analog 7i also exhibited GI 50 values 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 (AP 50  = 1.75 μM and 3.3 μM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI 50  = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI 50  = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI 50  = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI 50  = 0.22 μM), melanoma MDA-MB-435 (GI 50  = 0.22 μM), and breast cancer HS 578T (GI 50  = 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.