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Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2014 Oct 15; Vol. 24 (20), pp. 4818-21. Date of Electronic Publication: 2014 Sep 06. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Subjects :
- Alkaloids chemistry
Alkaloids isolation & purification
Amides chemistry
Amides isolation & purification
Antineoplastic Agents, Phytogenic chemistry
Antineoplastic Agents, Phytogenic isolation & purification
Cell Line, Tumor
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
MCF-7 Cells
Molecular Structure
Structure-Activity Relationship
Alkaloids pharmacology
Amides pharmacology
Antineoplastic Agents, Phytogenic pharmacology
Drug Resistance, Multiple drug effects
Drug Resistance, Neoplasm drug effects
Piper chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 24
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 25241925
- Full Text :
- https://doi.org/10.1016/j.bmcl.2014.08.063