Deuteration of the farnesyl terminal methyl groups of δ-tocotrienol and its effects on the metabolic stability and ability of inducing G-CSF production

Bioorg Med Chem. 2020 Jun 1;28(11):115498. doi: 10.1016/j.bmc.2020.115498. Epub 2020 Apr 8.

Abstract

δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability of DT3, a deuterium substituted DT3 derivative, d6-DT3, was designed and synthesized. d6-DT3 showed improved in vitro and in vivo metabolic stability compared to DT3. The unexpected lower potency of d6-DT3 in inducing granulocyte-colony stimulating factor (G-CSF) production in mouse revealed that the metabolite(s) of DT3 might play a major role in inducing G-CSF induction.

Keywords: Deuteration; Metabolic stability; Pharmacokinetics; Radio-protector; Tocotrienol.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Granulocyte Colony-Stimulating Factor / biosynthesis*
  • Male
  • Mice
  • Molecular Structure
  • Radiation-Protective Agents / chemistry
  • Radiation-Protective Agents / metabolism
  • Radiation-Protective Agents / pharmacology*
  • Structure-Activity Relationship
  • Vitamin E / analogs & derivatives*
  • Vitamin E / chemistry
  • Vitamin E / metabolism
  • Vitamin E / pharmacology

Substances

  • Radiation-Protective Agents
  • Vitamin E
  • Granulocyte Colony-Stimulating Factor
  • tocotrienol, delta