Abdel-Hamid Mohammed K, Abdel-Hafez Atef A, El-Koussi Nawal A, Mahfouz Nadia M, Innocenti Alessio, Supuran Claudiu T
Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
Bioorg Med Chem. 2007 Nov 15;15(22):6975-84. doi: 10.1016/j.bmc.2007.07.044. Epub 2007 Aug 22.
A new series of 1,3,4-thiadiazole-2-thione derivatives have been prepared and assayed for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. Against hCA I the investigated thiones, showed inhibition constants in the range of 2.55-222 microM, against hCA II in the range of 2.0-433 microM, and against hCA IX in the range of 1.25-148 microM. Compound 5c, 4-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)-1-(5-nitro-2-oxoindolin-3-ylidene)semicarbazide showed interesting inhibition of the tumor-associated hCA IX with K(I) value of 1.25 microM, being the first non-sulfonamide type inhibitor of such activity. This result is rather important taking into consideration the known antitumor activity of thiones. In addition, docking of the tested compounds into CA II active site was performed in order to predict the affinity and orientation of these compounds at the isozyme active site. The results showed similar orientation of the target compounds at CA II active site compared with reported sulfonamide type CAIs with the thione group acting as a zinc-binding moiety.
已制备了一系列新型的1,3,4-噻二唑-2-硫酮衍生物，并对其抑制三种生理相关碳酸酐酶（CA，EC 4.2.1.1）同工酶的活性进行了测定，这三种同工酶分别是胞质人同工酶I和II以及跨膜的肿瘤相关hCA IX。所研究的硫酮类化合物对hCA I的抑制常数在2.55 - 222 microM范围内，对hCA II的抑制常数在2.0 - 433 microM范围内，对hCA IX的抑制常数在1.25 - 148 microM范围内。化合物5c，即4-(4,5-二氢-5-硫代-1,3,4-噻二唑-2-基)-1-(5-硝基-2-氧代吲哚啉-3-亚基)氨基脲，对肿瘤相关的hCA IX表现出有趣的抑制作用，其K(I)值为1.25 microM，是此类活性的首个非磺酰胺类抑制剂。考虑到硫酮类化合物已知的抗肿瘤活性，这一结果相当重要。此外，还对测试化合物与CA II活性位点进行了对接，以预测这些化合物在同工酶活性位点的亲和力和取向。结果表明，与报道的磺酰胺类CAIs相比，目标化合物在CA II活性位点的取向相似，硫酮基团作为锌结合部分。
