Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds
Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds
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DOI：
10.1016/s0223-5234(02)01414-9
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发表时间：
2002-12-01
影响因子：
6.7
通讯作者：
Stables, JP
中科院分区：
文献类型：
--
作者：
Dimmock, JR;Jha, A;Stables, JP
合成了一系列4-羧基查尔酮1，并将其与3，5-双（苯亚甲基）-4-哌啶酮（2）偶联，得到一系列新的N-[4-（3-芳基-3-氧代-1-丙烯基）苯羰基]-3，5-双（苯亚甲基）-4-哌啶酮（3）。酰胺3的分子简化导致形成相应的N-（3-芳基-1-氧代-2-丙烯基）-3，5-双（苯基亚甲基）-4-哌啶酮（4）。系列1-4中的化合物的细胞毒性评价使用鼠P388和L1210细胞以及人Molt 4/C8和CEM T淋巴细胞。一般来说，化合物显示出显著的毒性;当考虑所有四种筛选时，54%的烯酮的IC（50）值小于10 μ M，并且在P388测定中，系列3的所有成员的IC（50）值小于1 μ M。在系列1、3和4中的化合物的效力与芳基取代基的Hammett σ、Hansch pi和分子生物活性常数之间建立了各种相关性。系列3和4中的五个代表性化合物的几个扭转角和原子间距离通过X射线晶体学测定，其中一些有助于观察到的生物活性。本研究中描述的大多数化合物的显著的细胞毒性和缺乏鼠毒性，以及它们对不同肿瘤细胞系的选择性毒性，揭示了应继续开发烯酮2-4作为新的候选抗癌剂。(C)2002年，Elsevier SAS科学与医学版。All rights reserved.
A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC(50) values of 54% of the enones were less than 10 muM when all four screens were considered and less than 1 muM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett sigma, Hansch pi and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.