Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain.
J Med Chem. 2010 Sep 23;53(18):6560-71. doi: 10.1021/jm100398z.
Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro.
继我们先前对抗炎药物（非甾体抗炎药）的研究之后，我们报告了 4-（芳基酰基）苯基甲基砜的设计和合成。这些物质的特征是它们抑制环氧化酶（COX-1 和 COX-2）同工酶的能力。分子建模研究表明，这些化合物的甲基砜基团插入到人 COX-2 结合部位的口袋深处，其取向阻止通过其氧原子与 Arg120、Ser353 和 Tyr355 形成氢键。N-芳基吲哚 33 是 COX-2 的最强抑制剂，也是最具选择性的（COX-1/COX-2 IC50 比值为 262）。吲哚衍生物 33 进一步在体内测试其在大鼠中的抗炎活性。该化合物显示出比布洛芬更强的抑制活性。其他化合物（20、26、9 和 30）对角叉菜胶诱导的炎症显示出很强的活性。后一类化合物在体外对人细胞系 K562、NCI-H460 和 HT-29 的增殖具有较弱的抑制能力。
