Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues.

Abstract

Twenty-five amide alkaloids (1-25) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives (39-48) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine (46) exhibited the best inhibitory activity (IC50=4.94 μM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC50 >40 μM) against MDA-MB-231 and SK-BR-3. Structure-activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype.

• Authors: Yue-Hu Wang, Masuo Goto, Li-Ting Wang, Kan-Yen Hsieh, Susan L Morris-Natschke, Gui-Hua Tang, Chun-Lin Long, Kuo-Hsiung Lee
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 20 Pg. 4818-21 (Oct 15 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 25241925 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Alkaloids
• Amides
• Antineoplastic Agents, Phytogenic

Topics

• Alkaloids (chemistry, isolation & purification, pharmacology)
• Amides (chemistry, isolation & purification, pharmacology)
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• MCF-7 Cells
• Molecular Structure
• Piper (chemistry)
• Structure-Activity Relationship