Thiopurines are in widespread clinical use for the treatment of immunological disorders and certain cancers. However, treatment failure due to resistance or adverse drug reactions are common, asking for new therapeutic strategies. We investigated the potential of 6-thioguanosine monophosphate (6sGMP) prodrugs to overcome resistance to 6-thioguanine. We successfully developed synthetic routes toward diverse 6sGMP prodrugs, tested their proliferation inhibitory potential in different cell lines, and examined their mode of action. Our results show that 4-acetyloxybenzyl- and cycloSaligenyl-derivatized 6sGMP prodrugs are effective antiproliferative compounds in cells that are resistant to thiopurines. We find that resistance is related to the expression of salvage pathway enzyme HGPRT. Using TUC-seq DUAL, we demonstrate the intracellular conversion of 6sGMP prodrugs into bioactive 6sGTPs. Thus, our study offers a promising strategy for thiopurine therapy by using 6sGMP prodrugs, and it suggests TUC-seq DUAL as a simple and fast method to measure the success of thiopurine therapy.

中文翻译：

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6-硫鸟苷单磷酸盐前药显示出增强的抗硫嘌呤耐药白血病和乳腺癌细胞的性能

硫嘌呤在临床上广泛用于治疗免疫紊乱和某些癌症。然而，由于耐药或药物不良反应导致的治疗失败很常见，需要新的治疗策略。我们研究了 6-硫鸟苷一磷酸 (6sGMP) 前药克服 6-硫鸟嘌呤抗性的潜力。我们成功地开发了多种 6sGMP 前药的合成路线，测试了它们在不同细胞系中的增殖抑制潜力，并检查了它们的作用方式。我们的结果表明，4-乙酰氧基苄基和环水杨基衍生的 6sGMP 前药是对硫嘌呤具有抗性的细胞中有效的抗增殖化合物。我们发现耐药性与补救途径酶 HGPRT 的表达有关。使用 TUC-seq DUAL，我们证明了 6sGMP 前药在细胞内转化为具有生物活性的 6sGTP。因此，我们的研究通过使用 6sGMP 前药为硫嘌呤治疗提供了一个有前途的策略，它表明 TUC-seq DUAL 作为一种简单快速的方法来衡量硫嘌呤治疗的成功与否。