Wang Yue-Hu, Goto Masuo, Wang Li-Ting, Hsieh Kan-Yen, Morris-Natschke Susan L, Tang Gui-Hua, Long Chun-Lin, Lee Kuo-Hsiung
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
Bioorg Med Chem Lett. 2014 Oct 15;24(20):4818-21. doi: 10.1016/j.bmcl.2014.08.063. Epub 2014 Sep 6.
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.
对来自蜂叶胡椒的25种酰胺生物碱（1 - 25）和10种合成酰胺生物碱衍生物（39 - 48）进行了抗增殖活性评估，针对包括化学敏感和多药耐药（MDR）细胞系在内的8种人类肿瘤细胞系。结果显示出肿瘤类型选择性。1 - [7 - （3,4,5 - 三甲氧基苯基）庚酰基]哌啶（46）对过表达P - 糖蛋白（P - gp）的KBvin MDR亚系表现出最佳抑制活性（IC50 = 4.94 μM），而它和所有其他测试化合物，除了9，对MDA - MB - 231和SK - BR - 3均无活性（IC50 > 40 μM）。构效关系（SARs）表明：（i）3,4,5 - 三甲氧基苯基取代对于针对KBvin的选择性至关重要；（ii）这种模式中的4 - 甲氧基对于抗增殖活性至关重要；（iii）侧链中的双键对于活性不是必需的；（iv）在芳基烯基酰基酰胺生物碱中，用吡咯烷 - 1 - 基或哌啶 - 1 - 基取代异丁基氨基可显著提高活性。有必要对胡椒酰胺进行进一步研究，特别是侧链长度是否会影响克服MDR癌症表型的能力。
