Recent studies have demonstrated that Glycogen Synthase Kinase 3β (GSK-3β) is overexpressed in human colon and pancreatic carcinomas contributing to cancer cell proliferation and survival. Here, we report the design, synthesis, and biological evaluation of benzofuran-3-yl-(indol-3-yl) maleimides, potent GSK-3β inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3β and an enhanced selectivity against Cyclin-dependent Kinase 2 (CDK-2). Selected GSK-3β inhibitors were tested in the pancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. We determined that some of these compounds, namely compounds 5, 6, 11, 20 and 26, demonstrate antiproliferative activity against some or all of the pancreatic cancer cells at low micromolar to nanomolar concentrations. We found that the treatment of pancreatic cancer cells with GSK-3β inhibitors 5 and 26 resulted in suppression of GSK-3β activity and a distinct decrease of the X-linked Inhibitor of Apoptosis (XIAP) expression leading to significant apoptosis. The present data suggest a possible role for GSK-3β inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders.
We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT 2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT 2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyltrans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT 2C receptor agonists with selectivity over both 5-HT 2A and 5-HT 2B receptors in functional assays. The most promising compound is 37 with 120-and 14-fold selectivity over 5-HT 2A and 5-HT 2B , respectively (EC 50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
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