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

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10.1002/cmdc.201900676

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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.",

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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

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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