新型羟基肟醚连接的苯磺酰胺作为潜在的人碳酸酐酶IX/XII抑制剂的发现

Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors.

作者信息

Peerzada Mudasir Nabi, Vullo Daniela, Paoletti Niccolò, Bonardi Alessandro, Gratteri Paola, Supuran Claudiu T, Azam Amir

机构信息

Medicinal Chemistry and Drug Discovery Research Laboratory, Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.

出版信息

ACS Med Chem Lett. 2023 May 8;14(6):810-819. doi: 10.1021/acsmedchemlett.3c00094. eCollection 2023 Jun 8.

To discover novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors for cancer treatment, a series of 4-{4-[(hydroxyimino)methyl]piperazin-1-yl}benzenesulfonamides were designed and synthesized using SLC-0111 as the lead molecule. The developed novel compounds - were investigated for the inhibition of human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. The hCA I was inhibited by compound with a value of 3.0 nM, whereas hCA II was inhibited by compound with a value of 4.4 nM. The tumor-associated hCA IX isoform was inhibited by compound effectively with an value of 43 nM, whereas the activity of another cancer-related isoform, hCA XII, was significantly inhibited by and with a value of 5 nM. Molecular modeling showed that drug molecule participates in significant hydrophobic and hydrogen bond interactions with the active site of the investigated hCAs and binds to zinc through the deprotonated sulfonamide group.

为发现用于癌症治疗的新型碳酸酐酶（CA，EC 4.2.1.1）抑制剂，以SLC-0111作为先导分子设计并合成了一系列4-{4-[(羟基亚氨基)甲基]哌嗪-1-基}苯磺酰胺。对所开发的新型化合物进行了抑制人（h）同工型hCA I、hCA II、hCA IX和hCA XII的研究。化合物对hCA I的抑制常数为3.0 nM，而化合物对hCA II的抑制常数为4.4 nM。肿瘤相关的hCA IX同工型被化合物有效抑制，抑制常数为43 nM，而另一种癌症相关同工型hCA XII的活性被化合物和显著抑制，抑制常数为5 nM。分子模拟表明，药物分子与所研究的hCAs的活性位点参与了显著的疏水和氢键相互作用，并通过去质子化的磺酰胺基团与锌结合。