School of Sciences, Indiana University Kokomo, Kokomo, Indiana 46904, United States.
Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada.
Curr Med Chem. 2021;28(13):2453-2464. doi: 10.2174/0929867327666200730215752.
This review outlines the discovery and development of a novel series of 1-[4-2- aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-piperidones (5-8) as potential drug candidates over the last 15 years in our laboratory. Many of these compounds demonstrate excellent cytotoxic properties and are often more potent than contemporary anticancer drugs. Two highly important features of many of these molecules are first, the greater tumour-selective toxicity and second, the ability of these molecules to act as modulators of multi-drug resistance. The modes of action of some of the potent compounds are by apoptosis induction, generation of reactive oxygen species, activation of certain caspases and affecting mitochondrial functions. These molecules also display promising antimalarial and antimycobacterial properties. In a short term toxicity study, these molecules are well tolerated in mice. Structure-activity relationships and a drug delivery system along with pharmacokinetic studies and metabolic stability of these compounds, have been presented. The positive characteristics associated with the series (5-8) warrant their further evaluations as candidate antineoplastic drug candidates.
这篇综述概述了在过去 15 年中，我们实验室在发现和开发一系列新型 1-[4-2-氨基乙氧基）苯基羰基]-3,5-双-（亚苄基）-4-哌啶酮（5-8）方面的进展，这些化合物作为潜在的药物候选物具有优异的细胞毒性。许多这些化合物具有很强的抗肿瘤活性，通常比当代抗癌药物更有效。这些分子的两个非常重要的特点是，首先是更大的肿瘤选择性毒性，其次是这些分子作为多药耐药性调节剂的能力。一些有效化合物的作用机制是通过诱导细胞凋亡、产生活性氧、激活某些半胱天冬酶和影响线粒体功能。这些分子还显示出有希望的抗疟疾和抗分枝杆菌特性。在一项短期毒性研究中，这些分子在小鼠中耐受良好。本文介绍了这些化合物的构效关系、药物传递系统以及药代动力学研究和代谢稳定性。该系列（5-8）具有的积极特性使其有必要进一步评估作为候选抗肿瘤药物。
