Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

Christina E. Mair; Rongxia Liu; Atanas G. Atanasov; Laurin Wimmer; Daniel Nemetz-Fiedler; Nadine Sider; Elke H. Heiss; Marko D. Mihovilovic; Verena M. Dirsch; Judith M. Rollinger

doi:10.1055/s-0035-1546165

Planta Medica, Table of Contents

Planta Med 2015; 81(12/13): 1065-1074
DOI: 10.1055/s-0035-1546165

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation^[*]

Christina E. Mair^#

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

²Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innsbruck, Austria

,

Rongxia Liu^#

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

⁴School of Pharmacy, Yantai University, Yantai, China

,

Atanas G. Atanasov

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

,

Laurin Wimmer

³Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria

,

Daniel Nemetz-Fiedler

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

,

Nadine Sider

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

,

Elke H. Heiss

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

,

Marko D. Mihovilovic

³Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria

,

Verena M. Dirsch

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

,

Judith M. Rollinger

¹Department of Pharmacognosy, University of Vienna, Vienna, Austria

²Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innsbruck, Austria

› Author Affiliations

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.

Key words

Piper nigrum - Piperaceae - Piperine - vascular smooth muscle cells - inhibition of VSMC proliferation - SAR - restenosis

Full Text

References

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Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation[*]

Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation^[*]