Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues |
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| Institution: | 1. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States;2. Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China;3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China;4. College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, People’s Republic of China;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 40447, Taiwan;1. College of Pharmacy, Catholic University of Daegu, Gyeongbuk 712-702, Republic of Korea;2. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea;3. College of Natural Science, Kangwon National University, Kangwon 200-701, Republic of Korea;1. Service de neurologie, hôpital Caremeau, CHU de Nîmes, 9, place du Prof.-R.-Debré, 30029 Nîmes cedex 9, France;2. Institut de génomique fonctionnelle, UMR5203, INSERM 1191, université de Montpellier, Montpellier, France;1. UMR 152 PharmaDev, Université de Toulouse, IRD, UPS, Toulouse, France;2. Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru;3. Institut de Chimie de Toulouse, ICT UAR 2599, Université Paul Sabatier-Toulouse III, Toulouse, France |
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| 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. |
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| Keywords: | Piperaceae Amide alkaloids Cytotoxicity Multidrug resistance |
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