Synthesis and Liver Microsomal Metabolic Stability Studies of a Fluorine-Substituted δ-Tocotrienol Derivative

Xingui Liu; Saikat Poddar; Lin Song; Howard Hendrickson; Xuan Zhang; Yaxia Yuan; Daohong Zhou; Guangrong Zheng

doi:10.1002/cmdc.201900676

Synthesis and Liver Microsomal Metabolic Stability Studies of a Fluorine-Substituted δ-Tocotrienol Derivative

Xingui Liu, Saikat Poddar, Lin Song, Howard Hendrickson, Xuan Zhang, Yaxia Yuan, Daohong Zhou, Guangrong Zheng

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

A fluoro-substituted δ-tocotrienol derivative, DT3-F2, was synthesized. This compound was designed to stabilize the metabolically labile terminal methyl groups of δ-tocotrienol by replacing one C−H bond on each of the two methyl groups with a C−F bond. However, in vitro metabolic stability studies using mouse liver microsomes revealed an unexpected rapid enzymatic C−F bond hydrolysis of DT3-F2. To the best of our knowledge, this is the first report of an unusual metabolic hydrolysis of allylic C−F bonds.

Original language	English (US)
Pages (from-to)	506-516
Number of pages	11
Journal	ChemMedChem
Volume	15
Issue number	6
DOIs	https://doi.org/10.1002/cmdc.201900676
State	Published - Mar 18 2020
Externally published	Yes

Keywords

C−F bond hydrolysis
fluorination
metabolic stability
synthesis
tocotrienol

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Organic Chemistry

Access to Document

10.1002/cmdc.201900676

Cite this

@article{97e4a5b9137a494abdfa6feb19707ee2,

title = "Synthesis and Liver Microsomal Metabolic Stability Studies of a Fluorine-Substituted δ-Tocotrienol Derivative",

abstract = "A fluoro-substituted δ-tocotrienol derivative, DT3-F2, was synthesized. This compound was designed to stabilize the metabolically labile terminal methyl groups of δ-tocotrienol by replacing one C−H bond on each of the two methyl groups with a C−F bond. However, in vitro metabolic stability studies using mouse liver microsomes revealed an unexpected rapid enzymatic C−F bond hydrolysis of DT3-F2. To the best of our knowledge, this is the first report of an unusual metabolic hydrolysis of allylic C−F bonds.",

keywords = "C−F bond hydrolysis, fluorination, metabolic stability, synthesis, tocotrienol",

author = "Xingui Liu and Saikat Poddar and Lin Song and Howard Hendrickson and Xuan Zhang and Yaxia Yuan and Daohong Zhou and Guangrong Zheng",

note = "Publisher Copyright: {\textcopyright} 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

year = "2020",

month = mar,

day = "18",

doi = "10.1002/cmdc.201900676",

language = "English (US)",

volume = "15",

pages = "506--516",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "John Wiley and Sons Ltd",

number = "6",

}

TY - JOUR

T1 - Synthesis and Liver Microsomal Metabolic Stability Studies of a Fluorine-Substituted δ-Tocotrienol Derivative

AU - Liu, Xingui

AU - Poddar, Saikat

AU - Song, Lin

AU - Hendrickson, Howard

AU - Zhang, Xuan

AU - Yuan, Yaxia

AU - Zhou, Daohong

AU - Zheng, Guangrong

PY - 2020/3/18

Y1 - 2020/3/18

N2 - A fluoro-substituted δ-tocotrienol derivative, DT3-F2, was synthesized. This compound was designed to stabilize the metabolically labile terminal methyl groups of δ-tocotrienol by replacing one C−H bond on each of the two methyl groups with a C−F bond. However, in vitro metabolic stability studies using mouse liver microsomes revealed an unexpected rapid enzymatic C−F bond hydrolysis of DT3-F2. To the best of our knowledge, this is the first report of an unusual metabolic hydrolysis of allylic C−F bonds.

AB - A fluoro-substituted δ-tocotrienol derivative, DT3-F2, was synthesized. This compound was designed to stabilize the metabolically labile terminal methyl groups of δ-tocotrienol by replacing one C−H bond on each of the two methyl groups with a C−F bond. However, in vitro metabolic stability studies using mouse liver microsomes revealed an unexpected rapid enzymatic C−F bond hydrolysis of DT3-F2. To the best of our knowledge, this is the first report of an unusual metabolic hydrolysis of allylic C−F bonds.

KW - C−F bond hydrolysis

KW - fluorination

KW - metabolic stability

KW - synthesis

KW - tocotrienol

UR - http://www.scopus.com/inward/record.url?scp=85079456144&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85079456144&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201900676

DO - 10.1002/cmdc.201900676

M3 - Article

C2 - 31957223

AN - SCOPUS:85079456144

SN - 1860-7179

VL - 15

SP - 506

EP - 516

JO - ChemMedChem

JF - ChemMedChem

IS - 6

ER -

Synthesis and Liver Microsomal Metabolic Stability Studies of a Fluorine-Substituted δ-Tocotrienol Derivative

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this