持续探索磺基香豆素作为肿瘤相关人碳酸酐酶 IX 和 XII 的选择性抑制剂。

Continued Structural Exploration of Sulfocoumarin as Selective Inhibitor of Tumor-Associated Human Carbonic Anhydrases IX and XII.

机构信息

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy.

Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.

出版信息

Molecules. 2022 Jun 24;27(13):4076. doi: 10.3390/molecules27134076.

A series of new 3- and 7-substituted sulfocoumarins was obtained by several cyclization reactions and subsequent derivatization for screening as prodrug inhibitors of the human (h) cancer-associated carbonic anhydrases (CAs) IX and XII. All products were ineffective inhibitors against the off-target hCA I and II, whilst hCAs IX and XII were inhibited with inhibition constants (KIs) spanning from low nanomolar to the high micromolar range, according to the sulfocoumarin derivatization pattern. In particular, sulfocoumarin 15 turned out to be the most potent and selective inhibitor herein reported (hCA I and II: KI > 100 µM; hCA IX: KI = 22.9 nM; hCA XII: KI = 19.2 nM). Considering that hCA IX and XII validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here may be useful for identifying suitable drug candidates for clinical trials.

通过一系列的环化反应和后续的衍生化，得到了一系列的 3-和 7-取代的磺基香豆素，用于筛选作为人（h）癌症相关碳酸酐酶（CA）IX 和 XII 的前药抑制剂。所有产物对非靶标 hCA I 和 II 均无抑制作用，而 hCA IX 和 XII 的抑制常数（KIs）范围从低纳摩尔到高微摩尔，这取决于磺基香豆素的衍生化模式。特别是磺基香豆素 15 是迄今为止报道的最有效和选择性的抑制剂（hCA I 和 II：KI > 100 µM；hCA IX：KI = 22.9 nM；hCA XII：KI = 19.2 nM）。鉴于 hCA IX 和 XII 是验证的抗肿瘤靶标，因此，这里报道的这种前药、同种型选择性抑制剂可能有助于确定适合临床试验的候选药物。