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.

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

“…176 Since 160 was mutagenic upon metabolic activation in susceptible bacteria, a mechanism was proposed that involved the formation of chemical intermediates that would react with genetic material. The postulated mechanism, which was informed by the known chemical toxicology of 161 and 162, involved oxidation of 160 to fluoroethylene oxide (166) followed by conversion to fluoroacetaldehyde (6) and fluoroacetic acid (5) (Scheme 23). 180,181 The enzyme responsible for the initial epoxidation was CYP2E1, which is expressed in the target tissues (e.g., liver, lung) of nonclinical species and is known to prefer small xenobiotics as substrates.…”

“…Simpler allylic fluorides lacking the activation afforded by the carbonyl moiety of 145 have also been observed to undergo hydrolytic cleavage of the C−F bond in mouse liver microsomes. 166 3. FLUORINATED ALKENES 3.1.…”

A Facile Semisynthesis and Evaluation of Garcinoic Acid and Its Analogs for the Inhibition of Human DNA Polymerase β

“…We have been using DT3 ( 3 ) as a starting material to synthesize its derivatives [ 17 , 18 , 19 ]. Garcinoic acid can be considered as the long-chain metabolite of DT3 resulting from ω-hydroxylation and ω-oxidation of DT3 and differs from DT3 only by bearing a trans -13′-carboxylic acid group [ 20 ].…”

Concise Synthesis of (S)-δ-CEHC, a Metabolite of Vitamin E

“…1 H NMR (400 MHz, CDCl 3 ) δ 6.47 (d, J = 3.0 Hz, 1H), 6.38 (d, J = 3.1 Hz, 1H), 3.72−3.62 (m, 2H), 2.81−2.61 (m, 2H), 2.11 (s, 3H), 1.86−1.60 (m, 6H), 1.25 (s, 3H). 13 (S)-3-(6-((tert-Butyldimethylsilyl)oxy)-2,8-dimethylchroman-2-yl)propan-1-ol (18). A mixture of (S)-8 (120 mg, 0.51 mmol), TBSCl (227 mg, 1.51 mmol), and imidazole (136 mg, 2.00 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with ethyl acetate × 2.…”

“…We are particularly interested in δ-tocotrienol (DT3) and its metabolic pathway. 17 , 18 DT3 and γ-tocotrienol have been studied for their radioprotective effects. 19 In addition, DT3 is the most potent VE homolog in the prevention and treatment of pancreatic cancer, 20 which supports the further preclinical investigations of DT3 and its metabolites in tumorigenesis.…”