31766-74-2Relevant articles and documents
N-heterocyclic carbene capture by cytochrome P450 3A4
Jennings, Gareth K.,Ritchie, Caroline M.,Shock, Lisa S.,Lyons, Charles E.,Hackett, John C.
, p. 42 - 51 (2016)
Cytochrome P450 3A4 (CYP3A4) is the dominant P450 enzyme involved in human drug metabolism, and its inhibition may result in adverse interactions or, conversely, favorably reduce the systemic elimination rates of poorly bioavailable drugs. Herein we describe a spectroscopic investigation of the interaction of CYP3A4 with N-methylritonavir, an analog of ritonavir, widely used as a pharmacoenhancer. In contrast to ritonavir, the binding affinity of N-methylritonavir for CYP3A4 is pH-dependent. At pH a red-shifted component characteristic of a P450- carbene complex. Variable-pH UV-visible spectroscopy binding studies with molecular fragments narrows the source of this pH dependence to its N-methylthiazolium fragment. The C2 proton of this group is acidic, and variable-pH resonance Raman spectroscopy tentatively assigns it a pKa of 7.4. Hence, this fragment of N-methylritonavir is expected to be readily deprotonated under physiologic conditions to yield a thiazol-2- ylidene, which is an N-heterocyclic carbene that has highaffinity for and is presumed to be subsequently captured by the heme iron. This mechanism is supported by time-dependent density functional theory with an active site model that accurately reproduces distinguishing features of the experimental UV-visible spectra of N-methylritonavir bound to CYP3A4. Finally, density functional theory calculations support that this novel interaction is as strong as the tightest-binding azaheterocycles found in P450 inhibitors and could offer new avenues for inhibitor development.
Synthesis and Characterization of Thiazepine/Benzothiazepine Derivatives Through Intramolecular C-2 Ring Expansion Pathway
Preet, Simer,Cannoo, Damanjt Singh
, p. 296 - 302 (2017/03/27)
A facile and highly efficient one-pot synthesis of novel thiazepine and benzothiazepine derivatives was established by ring expansion. With a greener methodology (ultrasonication), a polysubstituted ring system with the thiazepine core moiety can be easily synthesized from simple and easily available reactants in good yields. Moreover, the synthesized compounds show fluorescence and also antioxidant activity.