Rodil Andrea, Slawin Alexandra M Z, Al-Maharik Nawaf, Tomita Ren, O'Hagan David
School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK.
An Najah National University, Nablus, Palestine.
Beilstein J Org Chem. 2019 Jun 28;15:1441-1447. doi: 10.3762/bjoc.15.144. eCollection 2019.
We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substituent for bioactives discovery chemistry. Incubation of two aryl-SCFCH ethers with the model yeast organism indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more slowly to the sulfone. When the substrate was (OMe)PhSCFCH, then the resultant (demethylated) phenol sulfoxide had an enantiomeric excess of 60%, and when the substrate was the β-substituted-SCFCH naphthalene, then the enantiomeric excess of the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether (OMe)PhOCFCH, which was converted to the (demethylated) phenol acetate ester during incubation. We conclude that the aryl-S-CFCH motif is metabolised in a similar manner to aryl-SCF, a motif that is being widely explored in discovery chemistry. It is however, significantly less lipophilic than aryl-SCF which may offer a practical advantage in tuning overall pharmacokinetic profiles of molecules in development.
我们报告了最近引入的α,α-二氟乙硫醚基序的代谢情况，以进一步探索其作为生物活性物质发现化学中的取代基的潜力。将两种芳基-SCFCH醚与模式酵母生物体一起孵育表明，硫醚中的硫迅速转化为相应的亚砜，然后再缓慢得多地转化为砜。当底物为(OMe)PhSCFCH时，所得的（去甲基化）苯酚亚砜的对映体过量为60%，而当底物为β-取代的-SCFCH萘时，所得亚砜的对映体过量为54%。与相应的氧醚(OMe)PhOCFCH不同，没有脱氟的证据，(OMe)PhOCFCH在孵育过程中转化为（去甲基化）苯酚乙酸酯。我们得出结论，芳基-S-CFCH基序的代谢方式与芳基-SCF相似，芳基-SCF基序正在发现化学中得到广泛探索。然而，它的亲脂性明显低于芳基-SCF，这可能在调节正在开发的分子的整体药代动力学特征方面具有实际优势。
