Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, Puebla, México.
BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Universidad de La Laguna, La Laguna, Spain.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):168-177. doi: 10.1080/14756366.2021.1998026.
We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII ( within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII ( > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.
我们设计、合成并评价了一个包含 2-氨基苯并恶唑取代香豆素的小分子库，作为新型肿瘤相关 CAIX 和 CAXII 的抑制剂。香豆素骨架的 C-3 和/或 C-4 位以及苯并恶唑部分上的取代基，以及连接两个单元的连接链的长度都进行了修饰，以获得有用的构效关系。CA 抑制研究显示，与 CA I、II、IV 和 VII（>10μM）相比，这些化合物对肿瘤相关的 CAIX 和 CAXII 具有较好的选择性（大多数情况下为中纳摩尔范围）；CAIX 对结构变化的敏感性略高。对接计算表明，香豆素骨架可能作为前药起作用，以其水解形式与 CA 结合，这是由于 CA 的酯酶活性所致。增加连接链的长度和取代基的空间位阻被发现对增殖活性有害。在香豆素部分的 C-3 上引入氯原子可获得最强的增殖抑制剂，在所测试的肿瘤细胞系中，其活性处于低微摩尔范围内。
