Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

Abstract

Successful vascular healing after percutaneous coronary interventions is related to the inhibition of abnormal vascular smooth muscle cell proliferation and efficient re-endothelialization. In the search for vascular smooth muscle cell anti-proliferative agents from natural sources we identified piperine (1), the main pungent constituent of the fruits from Piper nigrum (black pepper). Piperine inhibited vascular smooth muscle cell proliferation with an IC50 of 21.6 µM, as quantified by a resazurin conversion assay. Investigations of ten piperamides isolated from black pepper fruits and 15 synthesized piperine derivatives resulted in the identification of three potent vascular smooth muscle cell proliferation inhibitors: the natural alkaloid pipertipine (4), and the two synthetic derivatives (2E,4E)-N,N-dibutyl-5-(3,5-dimethoxyphenyl)penta-2,4-dienamide (14) and (E)-N,N-dibutyl-3-(naphtho[2,3-d][1,3]dioxol-5-yl)acrylamide (20). They showed IC50 values of 3.38, 6.00, and 7.85 µM, respectively. Furthermore, the synthetic compound (2E,4E)-5-(4-fluorophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (12) was found to be cell type selective, by inhibiting vascular smooth muscle cell proliferation with an IC50 of 11.8 µM without influencing the growth of human endothelial cells.

Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor

“…VSMC proliferation was assessed by resazurin conversion . VSMCs were seeded at a density of 5 × 10 3 cells per well in transparent 96‐well plates.…”

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

“…Activation of α7nAChRs is likely to only inhibit the PDGF‐BB‐induced changes in the migration‐related signalling pathway in VSMCs. Previously, a lot of chemical compounds such as atorvastatin and apamin displayed inhibitory effects on both PDGF‐BB‐induced VSMC migration and proliferation (Chen et al, ; Kim et al, ; Mair et al, ). These dual actions on VSMC migration and proliferation were always mediated by mitogenic signalling pathways such as ERK1/2 and Akt (Chen et al, ; Kim et al, ).…”

Plant‐Derived Products for Treatment of Vascular Intima Hyperplasia Selectively Inhibit Vascular Smooth Muscle Cell Functions

“…For vascular IH, some studies indicate that alkaloids hinder cell cycle progress, decrease ROS production, and inhibit VSMC migration ( Table 4 ). A classic alkaloid, piperine, selectively inhibits VSMC proliferation with an IC50 of 11.8 μ mol/L without influencing VEC growth [ 94 ]. Coptisine was isolated from Coptis chinensis and suppresses VSMC proliferation selectively at lower concentrations with a GI 50 of 3.3 µ mol/L (1.2 µ g/mL) [ 95 ].…”