新型 1-[3-{3,5-双(亚苄基)-4-氧代-1-哌啶基}-3-氧代丙基]-4-哌啶酮肟及其相关季铵盐的设计、合成与肿瘤选择性毒性。

Design, Synthesis and Tumour-Selective Toxicity of Novel 1-[3-{3,5-Bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone Oximes and Related Quaternary Ammonium Salts.

机构信息

Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.

Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA.

出版信息

Molecules. 2021 Nov 25;26(23):7132. doi: 10.3390/molecules26237132.

DOI:10.3390/molecules26237132

PMID:34885719

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8659243/

Abstract

A novel series of 1-[3-{3,5-bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone oximes - and related quaternary ammonium salts - were prepared as candidate antineoplastic agents. Evaluation against neoplastic Ca9-22, HSC-2 and HSC-4 cells revealed the compounds in series and to be potent cytotoxins with submicromolar CC values in virtually all cases. In contrast, the compounds were less cytocidal towards HGF, HPLF and HPC non-malignant cells revealing their tumour-selective toxicity. Quantitative structure-activity relationships revealed that, in general, both cytotoxic potency and selectivity index figures increased as the magnitude of the Hammett sigma values rose. In addition, - are cytotoxic towards a number of leukemic and colon cancer cells. , lowered the mitochondrial membrane potential in CEM cells, and induced transient G2/M accumulation in Ca9-22 cells. Five compounds, namely , and , were identified as lead molecules that have drug-like properties.

摘要

我们合成了一系列新型 1-[3-{3,5-双（亚苄基）-4-氧代-1-哌啶基}-3-氧代丙基}-4-哌啶酮肟-和相关的季铵盐-作为候选抗肿瘤药物。对肿瘤 Ca9-22、HSC-2 和 HSC-4 细胞的评估表明，该系列化合物和是有效的细胞毒素，在几乎所有情况下，CC 值均低于亚微摩尔。相比之下，这些化合物对 HGF、HPLF 和 HPC 非恶性细胞的细胞毒性较小，表明它们具有肿瘤选择性毒性。定量构效关系研究表明，一般来说，随着哈米特 sigma 值的增加，细胞毒性的效力和选择性指数都有所增加。此外，-对多种白血病和结肠癌细胞也具有细胞毒性。，降低了 CEM 细胞中的线粒体膜电位，而在 Ca9-22 细胞中诱导短暂的 G2/M 积累。五种化合物，即、、、和，被确定为具有类药性的先导分子。