title: 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.
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Mair
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Rongxia
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria.
authors.forename: Laurin
authors.initials: L
authors.lastname: Wimmer
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nemetz-Fiedler
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Nadine
authors.initials: N
authors.lastname: Sider
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria.
authors.forename: Marko D
authors.initials: MD
authors.lastname: Mihovilovic
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D052117:Benzodioxoles / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D005638:Fruit / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D029222:Piper nigrum / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D010880:Piperidines; D010936:Plant Extracts; D053284:Polyunsaturated Alkamides; C008922:piperine