Lassalas Pierrik, Oukoloff Killian, Makani Vishruti, James Michael, Tran Van, Yao Yuemang, Huang Longchuan, Vijayendran Krishna, Monti Ludovica, Trojanowski John Q, Lee Virginia M-Y, Kozlowski Marisa C, Smith Amos B, Brunden Kurt R, Ballatore Carlo
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
ACS Med Chem Lett. 2017 Jul 5;8(8):864-868. doi: 10.1021/acsmedchemlett.7b00212. eCollection 2017 Aug 10.
The oxetane ring serves as an isostere of the carbonyl moiety, suggesting that oxetan-3-ol may be considered as a potential surrogate of the carboxylic acid functional group. To investigate this structural unit, as well as thietan-3-ol and the corresponding sulfoxide and sulfone derivatives, as potential carboxylic acid bioisosteres, a set of model compounds has been designed, synthesized, and evaluated for physicochemical properties. Similar derivatives of the cyclooxygenase inhibitor, ibuprofen, were also synthesized and evaluated for inhibition of eicosanoid biosynthesis in vitro. Collectively, the data suggest that oxetan-3-ol, thietan-3-ol, and related structures hold promise as isosteric replacements of the carboxylic acid moiety.
氧杂环丁烷环作为羰基部分的电子等排体，这表明3-羟甲基氧杂环丁烷可被视为羧酸官能团的潜在替代物。为了研究这个结构单元以及硫杂环丁烷-3-醇及其相应的亚砜和砜衍生物作为潜在的羧酸生物电子等排体，已设计、合成了一组模型化合物并对其理化性质进行了评估。还合成了环氧化酶抑制剂布洛芬的类似衍生物，并对其体外抑制类花生酸生物合成的能力进行了评估。总体而言，数据表明3-羟甲基氧杂环丁烷、硫杂环丁烷-3-醇及相关结构有望作为羧酸部分的等排替代物。
