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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Wang, Yue-Hu^1,2  Goto, Masuo¹  Wang, Li-Ting¹  Hsieh, Kan-Yen¹  Morris-Natschke, Susan L.¹  Tang, Gui-Hua³  Long, Chun-Lin^2,4  Lee, Kuo-Hsiung^1,5 

[1] Univ N Carolina, Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA

[2] Chinese Acad Sci, Kunming Inst Bot, Key Lab Econ Plants & Biotechnol, Kunming 650201, Peoples R China

[3] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China

[4] Minzu Univ China, Coll Life & Environm Sci, Beijing 100081, Peoples R China

[5] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung 40447, Taiwan

关键词: Piper;    Piperaceae;    Amide alkaloids;    Cytotoxicity;    Multidrug resistance;   

DOI  :  10.1016/j.bmcl.2014.08.063

来源: Elsevier

【 摘 要 】

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 mu M) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC50 > 40 mu M) 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. (C) 2014 Elsevier Ltd. All rights reserved.

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