Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.

中文翻译：

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1,3-偶极环加成，HPLC对映体分离以及糖精/异恶唑和糖精/异恶唑啉衍生物作为选择性碳酸酐酶IX和XII抑制剂的对接研究。

通过1，3-偶极环加成反应合成了两个系列的糖精/异恶唑和糖精/异恶唑啉杂化物。这些新化合物显示出对纳摩尔浓度范围内与癌症相关的人类碳酸酐酶（hCA）IX和XII亚型的有效和选择性抑制活性，而对脱靶物（如hCA I和II）没有亲和力。毫克级最代表性化合物的连续对映体分离导致发现（S）-异构体比其相应的（R）-对映体更有效。最后，进行了分子建模研究，以定义那些区分碳酸酐酶人类同工型的结构要求。还筛选了两种纳摩尔hCA IX和XII抑制剂对低氧环境中对非肿瘤原代细胞（成纤维细胞）和对乳腺癌细胞系（MCF7）的选择性毒性。处理72小时后，证明这些化合物与阿霉素在MCF7细胞上有效结合。