开发基于氨基喹唑啉的羧酸为非经典碳酸酐酶IX和XII抑制剂。
Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors.
发表日期:2023 Dec
作者:
Zainab M Elsayed, Hadia Almahli, Alessio Nocentini, Andrea Ammara, Claudiu T Supuran, Wagdy M Eldehna, Sahar M Abou-Seri
来源:
J Enzym Inhib Med Ch
摘要:
作为我们不断努力寻找新型抑制癌症相关CA IX和XII亚型的候选抗癌药物的一部分,我们在这里描述了设计和合成2-芳基-喹唑啉-4-基氨基苯甲酸衍生物(6a-c,7a-c和8a-c)作为新型的非经典CA抑制剂。 鉴于其在抗癌药物发现和开发有效的CAIs方面的重要性,4-苯胺喹唑啉特权骨架在该研究中得到了利用。 然后,在苯胺基团的正交(6a-c),间位(7a-c)或邻位(8a-c)添加了自由羧酸官能团,以提供目标抑制剂。 所有化合物都被评估其对hCA I,II(胞质),IX和XII(跨膜,肿瘤相关)亚型的抑制活性。 此外,六种喹唑啉物质(6a-c,7b和8a-b)被NCI-USA选中,进行了对代表九个肿瘤子板块的59种人类癌细胞系的体外抗增殖活性评估。
As part of our ongoing endeavour to identify novel inhibitors of cancer-associated CA isoforms IX and XII as possible anticancer candidates, here we describe the design and synthesis of small library of 2-aryl-quinazolin-4-yl aminobenzoic acid derivatives (6a-c, 7a-c, and 8a-c) as new non-classical CA inhibitors. On account of its significance in the anticancer drug discovery and in the development of effective CAIs, the 4-anilinoquinazoline privileged scaffold was exploited in this study. Thereafter, the free carboxylic acid functionality was appended in the ortho (6a-c), meta (7a-c), or para-positon (8a-c) of the anilino motif to furnish the target inhibitors. All compounds were assessed for their inhibitory activities against the hCA I, II (cytosolic), IX, and XII (trans-membrane, tumour-associated) isoforms. Moreover, six quinazolines (6a-c, 7b, and 8a-b) were chosen by the NCI-USA for in vitro anti-proliferative activity evaluation against 59 human cancer cell lines representing nine tumour subpanels.