PDF(Pubmed)
Abstract：
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.
摘要：
肿瘤相关碳酸酐酶(CA)IX和XII已被认为是治疗缺氧肿瘤的潜在靶标。因此,考虑到色烯支架作为IX和XII亚型的选择性配体的高药理学潜力，两个化合物库，即2H-色烯和7H-呋喃-色烯衍生物，设计和合成了不同的替代模式。对新合成的化合物的结构进行了表征，它们的抑制效力和对人CA的选择性脱离了目标亚型I，评估了II和癌症相关的CA同工型IX和XII。大多数化合物抑制CA同种型IX和XII,对I和II同工酶没有活性。因此，虽然效力受到沿着色烯支架的取代模式的影响，选择性在系列中保持不变，证实了2H-色烯和7H-呋喃-色烯支架用于设计同工酶选择性抑制剂的高潜力。
