University of Florence, Department of Chemistry "Ugo Schiff", Via della Lastruccia 3-13, I-50019, Sesto Fiorentino, Italy.
NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139, Florence, Italy.
Eur J Med Chem. 2019 Nov 1;181:111586. doi: 10.1016/j.ejmech.2019.111586. Epub 2019 Aug 5.
We have synthetized a novel series of β-hydroxy tellurides bearing the benzenesulfonamide group as potent inhibitors of carbonic anhydrase enzymes. In a one pot procedure, we discovered both the ring opening reaction of the three-membered ring and the cleavage of the sulfonamide protecting moiety at the same time. Moreover, the first X-ray co-crystallographic structure of a β-hydroxy telluride derivative with hCA II is reported. The potent effects of these compounds against the tumor-associated hCA IX with low nanomolar constant inhibition values give the possibility to evaluate their activity in vitro using a breast cancer cell line (MDA-MB-231). Compounds 7e and 7g induced significant toxic effects against tumor cells after 48 h incubation in normoxic conditions killing over 50% of tumor cells at 3 μM, but their efficacy decreased in hypoxic conditions reaching the 50% of the tumor cell viability only at 30 μM. These unusual features make them interesting lead compounds to act as antitumor agents, not only as Carbonic Anhydrase IX inhibitors, but reasonably in different pathways, where hCA IX is not overexpressed.
我们合成了一系列新型的β-羟基碲化物，其中含有苯磺酰胺基团，是碳酸酐酶的有效抑制剂。在一锅法中，我们同时发现了三元环的开环反应和磺酰胺保护基的断裂。此外，还报道了首例与 hCA II 的β-羟基碲化物衍生物的 X 射线共结晶结构。这些化合物对肿瘤相关 hCA IX 的强烈抑制作用（抑制常数的纳摩尔值较低）使得有可能使用乳腺癌细胞系（MDA-MB-231）在体外评估它们的活性。在常氧条件下孵育 48 小时后，化合物 7e 和 7g 对肿瘤细胞产生了显著的毒性作用，在 3μM 时杀死了超过 50%的肿瘤细胞，但在缺氧条件下其疗效降低，仅在 30μM 时达到肿瘤细胞活力的 50%。这些不寻常的特征使它们成为有前途的抗肿瘤药物先导化合物，不仅作为碳酸酐酶 IX 抑制剂，而且在 hCA IX 未过度表达的不同途径中也具有合理的作用。
