Designing a novel photoinduced electron transfer-based small-molecule fluorescent probe specific for CYP3A isozymes

Bioorg Med Chem Lett. 2021 Sep 1:47:128195. doi: 10.1016/j.bmcl.2021.128195. Epub 2021 Jun 10.

Abstract

Cytochrome P450 (CYPs) are oxidoreductases distributed in various tissues in plants and animals. Among the CYP families, CYP3A is the most abundant in vivo, particularly in humans, and it is involved in the metabolism of many drugs. It is crucial to measure CYP3A activity for both pharmaceuticals and agrochemicals because inhibition or induction of this enzyme can seriously affect the occurrence of toxicity or efficacy. In the present study, a novel fluorescent probe, 6-(2,5-bis(trifluoromethyl)benzyloxy)-9-(4-methoxy-2-methylphenyl)-3H-xanthen-3-one (BMX, quantum efficiency: 21%), was designed and synthesized. The design was done by photoinduced electron transfer strategy. BMX was specifically metabolized only using CYP3A to generate 2-Me-4-MeO TokyoGreen (quantum efficiency: 85%), resulting in strong fluorescence in the presence of CYP3A isozymes. Protein assays using recombinant human, rat, and mouse CYP isozymes demonstrated the selective metabolism of BMX and production of fluorescence only by CYP3A in all species.

Keywords: CYP3A; Fluorescent prove; Photoinduced electron transfer (PeT).

MeSH terms

  • Cytochrome P-450 CYP3A / analysis*
  • Cytochrome P-450 CYP3A / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Electron Transport
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / chemistry*
  • Humans
  • Molecular Structure
  • Photochemical Processes
  • Structure-Activity Relationship
  • Xanthenes / chemical synthesis
  • Xanthenes / chemistry*

Substances

  • Fluorescent Dyes
  • Xanthenes
  • Cytochrome P-450 CYP3A