双[3,5-双(亚苄基)-4-氧代-1-哌啶基]酰胺：一类新型强效细胞毒素。
Bis[3,5-bis(benzylidene)-4-oxo-1-piperidinyl]amides: a novel class of potent cytotoxins.
机构信息
Drug Design & Discovery Research Group, College of Pharmacy & Nutrition, University of Saskatchewan, 216 Thorvaldson, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
出版信息
ChemMedChem. 2011 Oct 4;6(10):1892-9. doi: 10.1002/cmdc.201100199. Epub 2011 Aug 8.
Abstract
The principal objective of this study was the examination of the theory of cytotoxic synergism. In this exploratory study, we tested the hypothesis that doubling the number of sites available for thiol alkylation in a series of candidate cytotoxins increases potency more than two-fold. This concept was verified in one-third of our comparisons using human Molt 4/C8 and CEM T-lymphocytes and murine L1210 cells. In addition, the significant potencies of various members of our compound series justified further studies. Molecular modeling revealed that relative locations of the amidic groups correlate with cytotoxicity. A potent cytotoxic compound, 1,2-bis(3,5-dibenzylidene-4-oxo-piperidin-1-yl)ethane-1,2-dione (1a) inhibited the growth of a large number of human tumor cell lines and displayed greater toxicity toward certain non-adherent cells than toward adherent neoplasms or fibroblasts. The mode of action of 1a includes induction of apoptosis and necrosis.
摘要
本研究的主要目的是检验细胞毒协同作用理论。在这项探索性研究中，我们检验了这样一个假设，即在一系列候选细胞毒素中，增加可供巯基烷基化的位点数量两倍以上，可使活性增加两倍以上。这一概念在使用人 Molt 4/C8 和 CEM T 淋巴细胞和鼠 L1210 细胞的三分之一比较中得到了验证。此外，我们化合物系列中各种成员的显著活性证明了进一步研究的合理性。分子建模表明，酰胺基团的相对位置与细胞毒性相关。一种有效的细胞毒化合物，1,2-双(3,5-二苄基-4-氧代-哌啶-1-基)乙烷-1,2-二酮（1a）抑制了大量人类肿瘤细胞系的生长，并显示出对某些非贴壁细胞的毒性大于对贴壁肿瘤或成纤维细胞的毒性。1a 的作用模式包括诱导细胞凋亡和坏死。
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