Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy.
CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2270183. doi: 10.1080/14756366.2023.2270183. Epub 2023 Oct 23.
Tumour associated carbonic anhydrases (CAs) IX and XII have been recognised as potential targets for the treatment of hypoxic tumours. Therefore, considering the high pharmacological potential of the chromene scaffold as selective ligand of the IX and XII isoforms, two libraries of compounds, namely 2H-chromene and 7H-furo-chromene derivatives, with diverse substitution patterns were designed and synthesised. The structure of the newly synthesised compounds was characterised and their inhibitory potency and selectivity towards human CA off target isoforms I, II and cancer-associated CA isoforms IX and XII were evaluated. Most of the compounds inhibit CA isoforms IX and XII with no activity against the I and II isozymes. Thus, while the potency was influenced by the substitution pattern along the chromene scaffold, the selectivity was conserved along the series, confirming the high potential of both 2H-chromene and 7H-furo-chromene scaffolds for the design of isozyme selective inhibitors.
肿瘤相关碳酸酐ases（CAs）IX 和 XII 已被认为是治疗缺氧肿瘤的潜在靶点。因此，考虑到色烯骨架作为 IX 和 XII 同工型的选择性配体具有很高的药理学潜力，设计并合成了两个化合物库，即 2H-色烯和 7H-呋喃色烯衍生物，具有不同的取代模式。新合成化合物的结构进行了表征，并评估了它们对人 CA 非靶标同工型 I、II 和癌症相关 CA 同工型 IX 和 XII 的抑制效力和选择性。大多数化合物抑制 CA 同工型 IX 和 XII，对 I 和 II 同工型没有活性。因此，虽然构效关系受到色烯骨架取代模式的影响，但整个系列中保持了选择性，证实了 2H-色烯和 7H-呋喃色烯骨架在设计同工型选择性抑制剂方面具有很高的潜力。
