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Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-28 , DOI: 10.1016/j.bmcl.2020.127148
Subha Bakthavatsalam 1 , Petpailin Wiangnak 1 , Daniel J George 2 , Tian Zhang 2 , Katherine J Franz 1
Affiliation  

Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram's therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC50 of HPD was 1.4 µM in PSA-expressing LNCaP cells, and 11 µM in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.

中文翻译:


二硫代氨基甲酸盐前药由前列腺特异性抗原激活以靶向前列腺癌。



双硫仑与铜结合已被证明是一种有效的抗癌剂。然而,双硫仑在前列腺癌中的治疗潜力因其含有反应性亲核硫醇成分二乙基二硫代氨基甲酸酯(DTC)而受到脱靶效应的阻碍。为了最大限度地减少不良反应,我们策略性地用可裂解的对氨基苯甲基 (pAB) 基团封闭了 DTC 中的硫醇部分,该基团与前列腺特异性抗原 (PSA) 识别的肽底物相连。在这里,我们报告了两种 PSA 可激活前药 HPD(Ac-HSSKLQL-pAB-DTC 和 RPD (RSSYYSL-pAB-DTC)在癌细胞模型中的合成和评估。体外暴露于 PSA 被发现会触发 HPD 和 RPD 的激活。 RPD 释放二乙基二硫代氨基甲酸酯,两种前药均被发现可在前列腺癌细胞中诱导毒性,其中 HPD 显示出最有希望的选择性,在补充铜的情况下,HPD 在表达 PSA 的 LNCaP 细胞中的 IC50 为 1.4 µM,在 PC3 细胞中为 11 µM。这些研究证明了使用肽识别手柄来指导二硫代氨基甲酸酯前药对癌细胞的选择性细胞毒性的活性。
更新日期:2020-04-20
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