University of Veterinary and Pharmaceutical Sciences, Faculty of Pharmacy, Department of Chemical Drugs, Palackého 1-3, CZ-612 42 Brno, Czech Republic; Masaryk University, Faculty of Science, Department of Chemistry, Centre for Syntheses at Sustainable Conditions and Their Management, University Campus, Kamenice 753/5, CZ-625 00 Brno, Czech Republic.
University of Veterinary and Pharmaceutical Sciences, Faculty of Pharmacy, Department of Chemical Drugs, Palackého 1-3, CZ-612 42 Brno, Czech Republic.
Bioorg Chem. 2018 Apr;77:25-37. doi: 10.1016/j.bioorg.2017.12.034. Epub 2018 Jan 3.
A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with Ks in the range of 8.5-2679.1 nM, hCA II with Ks in the range of 4.8-380.5 nM and hCA IX with Ks in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX.
报道了一系列新的三嗪衍生物，其中包含磺胺、磺胺甲噁唑、4-乙氨基苯磺酰胺和哌嗪或氨基醇结构基序。利用分子对接从虚拟组合库中选择化合物进行合成和随后的生物评价。这些化合物是通过氰尿酸氯（2,4,6-三氯-1,3,5-三嗪）中氯原子的逐步亲核取代制备的。这些化合物被测试为生理相关碳酸酐酶（CA，EC 4.2.1.1）同工酶的抑制剂。具体来说，针对细胞质 hCA I、II 和肿瘤相关 hCA IX。这些化合物表现出相当大的抑制作用。hCA I 的抑制常数（Ks）范围为 8.5-2679.1 nM，hCA II 的 Ks 范围为 4.8-380.5 nM，hCA IX 的 Ks 范围为 0.4-307.7 nM。与其他类似的衍生物一样，一些化合物对抑制 hCA IX 相对于 hCA II 的选择性比率为 3.5-18.5。4-[[（4-氯-6-（（4-羟基苯基）氨基）-1,3,5-三嗪-2-基）氨基]甲基]苯磺酰胺对 hCA IX（0.4 nM）具有亚纳摩尔亲和力，并对细胞质同工酶具有选择性（18.50）。该系列化合物可能对开发针对缺氧诱导的 CA 同工酶（如 CA IX）的新型非传统抗癌药物具有重要意义。
