Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.
Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.
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DOI：
10.1016/j.bmcl.2020.127148
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发表时间：
2020-06-01
影响因子：
2.7
通讯作者：
Franz KJ
中科院分区：
文献类型：
--
作者：
Bakthavatsalam S;Wiangnak P;George DJ;Zhang T;Franz KJ
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受到脱靶效应的阻碍，脱靶效应是由于双硫仑的反应性和亲核性含硫醇组分二乙基二硫代氨基甲酸酯（DTC）。为了最大限度地减少不良反应，我们已经战略性地阻断DTC中的巯基部分，其具有与前列腺特异性抗原（PSA）识别的肽底物连接的可裂解的对氨基苄基（pAB）基团。本文报道了两种PSA活化的前体药物HPD（Ac-HSSKLQL-pAB-DTC）和RPD（RSSYYSL-pAB-DTC）的合成及其在癌细胞模型中的评价。在体外暴露于PSA被发现触发激活的HPD和RPD释放二乙基二硫代氨基甲酸酯，并发现这两种前药诱导前列腺癌细胞的毒性，与HPD显示出最有前途的选择性。在铜补充的情况下，HPD的IC 50在PSA表达的LNCaP细胞中为1.4 μM，在不表达PSA的PC 3细胞中为11 μM。这些研究证明了使用肽识别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的实用性。
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.
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影响因子：
3.5
作者：
AKIYAMA, K;NAKAMURA, T;HARA, M
通讯作者：
HARA, M
影响因子：
158.5
作者：
Scher, Howard I.;Fizazi, Karim;de Bono, Johann S.
通讯作者：
de Bono, Johann S.
影响因子：
--
作者：
Denoyer D;Pearson HB;Clatworthy SA;Smith ZM;Francis PS;Llanos RM;Volitakis I;Phillips WA;Meggyesy PM;Masaldan S;Cater MA
通讯作者：
Cater MA
影响因子：
158.5
作者：
STAMEY, TA;YANG, N;REDWINE, E
通讯作者：
REDWINE, E
影响因子：
15.9
作者：
LILJA, H
通讯作者：
LILJA, H