Pingaew Ratchanok, Prachayasittikul Veda, Mandi Prasit, Nantasenamat Chanin, Prachayasittikul Supaluk, Ruchirawat Somsak, Prachayasittikul Virapong
Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand.
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Bioorg Med Chem. 2015 Jul 1;23(13):3472-80. doi: 10.1016/j.bmc.2015.04.036. Epub 2015 Apr 17.
A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC50=1.3-9.4μM). Interestingly, the meta analog of triazole-benzene-sulfonamide (34) bearing 6,7-dimethoxy substituents on the isoquinoline ring displayed the most potent aromatase inhibitory activity (IC50=0.2μM) without affecting normal cell. Molecular docking of these triazoles against aromatase revealed that the compounds could snugly occupy the active site of the enzyme through hydrophobic, π-π stacking, and hydrogen bonding interactions. The potent compound 34 was able to form hydrogen bonds with Met374 and Ser478 which were suggested to be the essential residues for the promising inhibition. The study provides compound 34 as a potential lead molecule of anti-aromatase agent for further development.
合成了一系列含有磺酰胺部分的1,4-二取代-1,2,3-三唑（13 - 35），并评估了它们的芳香酶抑制作用。大多数具有开链磺酰胺的三唑显示出显著的芳香酶抑制活性（IC50 = 1.3 - 9.4μM）。有趣的是，在异喹啉环上带有6,7-二甲氧基取代基的三唑-苯-磺酰胺（34）的间位类似物表现出最有效的芳香酶抑制活性（IC50 = 0.2μM），且不影响正常细胞。这些三唑与芳香酶的分子对接表明，化合物可通过疏水、π-π堆积和氢键相互作用紧密占据酶的活性位点。强效化合物34能够与Met374和Ser478形成氢键，这两个残基被认为是产生有效抑制作用的关键残基。该研究提供了化合物34作为抗芳香酶剂的潜在先导分子以供进一步开发。
