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

Liu, Xingui; Gao, Zhengya; Fu, Qiang; Song, Lin; Zhang, Peiyi; Zhang, Xuan; Hendrickson, Howard P.; Crooks, Peter A.; Zhou, Daohong; Zheng, Guangrong

doi:10.1016/j.bmc.2020.115498

Cited by 7 publications

(7 citation statements)

References 42 publications

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“…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 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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Garcinoic acid has been identified as an inhibitor of DNA polymerase β (pol β). However, no structure-activity relationship (SAR) studies of garcinoic acid as a pol β inhibitor have been conducted, in part due to the lack of an efficient synthetic method for this natural product and its analogs. We developed an efficient semi-synthetic method for garcinoic acid and its analogs by starting from natural product δ-tocotrienol. Our preliminary SAR studies provided a valuable insight into future discovery of garcinoic acid-based pol β inhibitors.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…Even when an informed decision on DKIEs is made, the impact of deuteration might not be the one expected, and translating deuterated compounds from bench to bedside is quite challenging. The reasons behind drug failure of deuterated analogues are diverse and include: deuterium-promoted multidirectional metabolic switching (for example, d 7 -doxophylline 145 ); reduced metabolite-induced efficacy in vivo (for example, d 1 -N-demethyldiazepam 146 , d 6 -δ-tocotrienol 147 ); masking of DKIE by competing conjugating enzymes or nonmetabolic elimination mechanisms (for example, deuterated analogues of propofol 148 ); and interspecies variability jeopardizing the predictivity of preclinical testing (for example, d 3 -imatinib 149 ).…”

Section: Opportunities and Challenges For Deuterationmentioning

confidence: 99%

Deuterium in drug discovery: progress, opportunities and challenges

Martino

Maxwell

Pirali

2023

Nat Rev Drug Discov

190

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Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.

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“…These differences are important when considering the disease-modifying and preventive effects of supplementation. Immunostimulation [40] Given the prominent role of oxidative stress, chronic inflammation and dyslipidemia in the pathophysiology of neurodegenerative diseases, vitamin E is considered a promising therapeutic strategy (Table 2). The definition of vitamin E and which derivates should be associated with this term are still under discussion.…”

Section: Characteristics Of Vitamin E In the Context Of Neurodegenerative Diseasesmentioning

confidence: 99%

Enjoy Carefully: The Multifaceted Role of Vitamin E in Neuro-Nutrition

Regner-Nelke

Nelke

Schroeter

et al. 2021

IJMS

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Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer’s or Parkinson’s disease. However, trials evaluating the effects of vitamin E supplementation are inconsistent. In randomized controlled trials, the observed associations often cannot be substantiated. This could be due to the wide variety of study designs regarding the dosage and duration of vitamin E supplementation. Furthermore, genetic variants can influence vitamin E uptake and/or metabolism, thereby distorting its overall effect. Recent studies also show adverse effects of vitamin E supplementation regarding Alzheimer’s disease due to the increased synthesis of amyloid β. These diverse effects may underline the inhomogeneous outcomes associated with its supplementation and argue for a more thoughtful usage of vitamin E. Specifically, the genetic and nutritional profile should be taken into consideration to identify suitable candidates who will benefit from supplementation. In this review, we will provide an overview of the current knowledge of vitamin E supplementation in neurodegenerative disease and give an outlook on individualized, sustainable neuro-nutrition, with a focus on vitamin E supplementation.

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

Cited by 7 publications

References 42 publications

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

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

Deuterium in drug discovery: progress, opportunities and challenges

Enjoy Carefully: The Multifaceted Role of Vitamin E in Neuro-Nutrition

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