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Design, synthesis, and evaluation of potential carbamate prodrugs of 5′-methylthioadenosine (MTA)
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2021-04-29 , DOI: 10.1007/s00044-021-02730-9
Ashwini Sadanand Ranade , Joseph R. Bertino , Longqin Hu

5′-Methylthioadenosine (MTA) is a natural substrate of MTA phosphorylase (MTAP) and is converted to adenine via a salvage pathway for AMP production in normal healthy cells. The lack of MTAP expression in many solid tumors and hematologic malignancies compared to normal healthy cells has been explored in a potential therapeutic strategy to selectively target tumor cells using antimetabolites such as 5-fluorouracil (5-FU) and 6-thioguanine (6-TG) while protecting normal healthy cells with MTA. Herein, a series of carbamate prodrugs, namely the N-(alkyloxy)carbonyl-MTA derivatives 2a-f, was designed, synthesized, and evaluated as potential prodrugs of MTA. All carbamate prodrugs were stable in phosphate buffer, pH 7.4 at 37 °C. In the presence of mouse liver microsomes, the prodrugs were converted to MTA at varying rates with the hexyl and butyl carbamates 2a and 2b most readily activated (t1/2 of 1.2 and 9.4 h, respectively). The activation was shown to be mediated by carboxyesterases present in mouse liver microsomes.



中文翻译:

5'-甲硫基腺苷(MTA)的潜在氨基甲酸酯前药的设计,合成和评估

5'-甲硫基腺苷(MTA)是MTA磷酸化酶(MTAP)的天然底物,可通过挽救途径转化为腺嘌呤,以在正常健康细胞中产生AMP。与正常健康细胞相比,在许多实体瘤和血液系统恶性肿瘤中缺乏MTAP表达已被研究为一种潜在的治疗策略,可使用抗代谢物(例如5-氟尿嘧啶(5-FU)和6-硫鸟嘌呤(6-TG)选择性靶向肿瘤细胞),同时使用MTA保护正常的健康细胞。在此,一系列氨基甲酸酯前药,即N-(烷氧基)羰基-MTA衍生物2a-f被设计,合成和评估为MTA的潜在前药。所有氨基甲酸酯前药在37°C的pH 7.4磷酸盐缓冲液中均稳定。在小鼠肝微粒体存在下,前药以不同的速率转化为MTA,氨基甲酸己酯和氨基甲酸丁酯2a2b最容易活化(分别为t 1/2的1.2和9.4 h)。显示该活化是由小鼠肝微粒体中存在的羧酯酶介导的。

更新日期:2021-04-29
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