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新型非对称 3,5-双（亚苄基）-4-哌啶酮，具有肿瘤选择性毒性。

Novel Unsymmetric 3,5-Bis(benzylidene)-4-piperidones That Display Tumor-Selective Toxicity.

机构信息

Department of Chemistry, Dyal Singh College, University of Delhi, New Delhi 110003, India.

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

出版信息

Molecules. 2022 Oct 9;27(19):6718. doi: 10.3390/molecules27196718.

DOI:10.3390/molecules27196718
PMID:36235258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9572513/
Abstract

Two series of novel unsymmetrical 3,5-bis(benzylidene)-4 piperidones - and - were designed as candidate antineoplastic agents. These compounds display potent cytotoxicity towards two colon cancers, as well as several oral squamous cell carcinomas. These compounds are less toxic to various non-malignant cells giving rise to large selectivity index (SI) figures. Many of the compounds are also cytotoxic towards CEM lymphoma and HL-60 leukemia cells. Representative compounds induced apoptotic cell death characterized by caspase-3 activation and subG1 accumulation in some OSCC cells, as well as the depolarization of the mitochondrial membrane potential in CEM cells. A further line of inquiry was directed to finding if the SI values are correlated with the atomic charges on the olefinic carbon atoms. The potential of these compounds as antineoplastic agents was enhanced by an ADME (absorption, distribution, metabolism, and excretion) evaluation of five lead molecules, which revealed no violations.

摘要

设计了两个系列新型非对称 3,5-双（亚苄基）-4-哌啶酮和-作为候选抗肿瘤药物。这些化合物对两种结肠癌以及几种口腔鳞状细胞癌表现出很强的细胞毒性。这些化合物对各种非恶性细胞的毒性较小，导致较大的选择性指数（SI）数值。许多化合物对 CEM 淋巴瘤和 HL-60 白血病细胞也具有细胞毒性。代表性化合物诱导细胞凋亡，特征是 caspase-3 激活和一些 OSCC 细胞中的 subG1 积累，以及 CEM 细胞中线粒体膜电位去极化。进一步的研究方向是确定 SI 值是否与双键碳原子上的原子电荷相关。通过对 5 种先导化合物进行吸收、分布、代谢和排泄（ADME）评估，增强了这些化合物作为抗肿瘤药物的潜力，结果显示没有违反规定。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/852cf5c203a9/molecules-27-06718-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/395f313470de/molecules-27-06718-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/add68b966fe5/molecules-27-06718-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/159739339779/molecules-27-06718-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/757acfc8879f/molecules-27-06718-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/9b939bbb8689/molecules-27-06718-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/f2d8924bb4aa/molecules-27-06718-g006a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/852cf5c203a9/molecules-27-06718-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/395f313470de/molecules-27-06718-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/add68b966fe5/molecules-27-06718-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/159739339779/molecules-27-06718-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/757acfc8879f/molecules-27-06718-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/9b939bbb8689/molecules-27-06718-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/f2d8924bb4aa/molecules-27-06718-g006a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a86/9572513/852cf5c203a9/molecules-27-06718-sch001.jpg

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Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment.结肠癌治疗中5-氟尿嘧啶耐药机制及逆转策略的最新进展
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