Structure-based design, synthesis, and biological evaluation of novel piperine-resveratrol hybrids as antiproliferative agents targeting SIRT-2

Abstract

A series of novel piperine-resveratrol hybrids5a-hwas designed, synthesized, and structurally elucidated by IR, and1H,13C, and19F NMR. Antiproliferative activities of5a-hwere evaluated by NCI against sixty cancer cell lines. Compound5b, possessing resveratrol pharmacophoric phenolic moieties, showed a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth inhibition percentage of −0.49 and −2.83, respectively. In addition,5brecorded significant activity against the other cancer cell lines with growth inhibition percentage between 80 to 95. New5a-hhybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their antiproliferative action. Results showed that compounds5a-hwere more potent inhibitors of Sirt-2 than Sirt-1 at 5 μm and 50 μm. Compound5bshowed the strongest inhibition of Sirt-2 (78 ± 3% and 26 ± 3% inhibition at 50 μM and 5 μM, respectively). Investigation of intermolecular interactionviaHirschfeld surface analysis indicates that these close contacts are mainly ascribed to the O-H⋯O hydrogen bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where5bwas found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with the substrate acyl-Lys. Another possible binding pattern showed that5bcould act by partial occlusion of the NAD+C-pocket. Collectively, these findings would contribute significantly to better understanding the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2 inhibitors.