SNM1A is a zinc-dependent nuclease involved in removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored. Herein, the synthesis of a family of squaramide- and thiosquaramide-bearing nucleoside derivatives and their evaluation as SNM1A inhibitors is reported. A gel electrophoresis assay was used to identify nucleoside derivatives bearing an N-hydroxysquaramide or squaric acid moiety at the 3’-position, and a thymidine derivative bearing a 5’-thiosquaramide, as candidate SNM1A inhibitors. Quantitative IC₅₀ determination showed that a thymidine derivative bearing a 5’–thiosquaramide was the most potent inhibitor, followed by a thymidine derivative bearing a 3’-squaric acid. UV-Vis titrations were carried out to evaluate the binding of the (thio)squaramides to zinc ions, allowing the order of inhibitory potency to be rationalised. The membrane permeability of the active inhibitors was investigated, with several compounds showing promise for future in vivo applications.

SNM1A 是一种锌依赖性核酸酶，参与从 DNA 中去除链间交联损伤。抑制链间交联修复酶如 SNM1A 是提高交联化疗药物疗效的有前途的策略。最初的研究已经证明了开发 SNM1A 抑制剂的可行性，但这种酶作为药物靶点的全部潜力还有待探索。在此，报道了带有方酸酰胺和硫代方酰胺的核苷衍生物家族的合成及其作为 SNM1A 抑制剂的评价。凝胶电泳分析用于鉴定在 3'-位带有N-羟基方酸酰胺或方酸部分的核苷衍生物，以及带有 5'-硫代方酸酰胺的胸苷衍生物，作为候选 SNM1A 抑制剂。定量IC₅₀测定表明，带有 5'-硫代方酸酰胺的胸苷衍生物是最有效的抑制剂，其次是带有 3'-方酸的胸苷衍生物。进行紫外-可见滴定以评估（硫代）方酸酰胺与锌离子的结合，从而使抑制效力的顺序合理化。研究了活性抑制剂的膜渗透性，其中几种化合物显示出未来体内应用的前景。