Ketone Ester Research Articles

Intragastric ketone ester administration prevents CNS oxygen toxicity (CNS‐OT) and modulates tidal volume and respiratory frequency in rats

In clinical and military operations, hyperbaric oxygen (HBO) can generate central nervous system oxygen toxicity (seizures). In a previous study, we demonstrated that the intragastric administration of ketone ester (KE), a non‐ionized ketone bodies precursor, has a prominent anti‐seizure effect. In this follow‐up study, we tested the anticonvulsant properties of multiple KEs, and their effects on cardio‐respiration.60 male rats were implanted with radio‐telemetry devices to record EEG, diaphragmatic electromyogram (dEMG) and ECG. Rats were orally administered with one of four KEs: beta hydroxybutyrate, R,S‐1,3‐butanediol, acetoacetate monoester (AcAc), and acetoacetate diester (AcAc2). 30 min later, rats were exposed to HBO at 5 atmosphere absolute, until the onset of CN‐SOT, and the latency to seizure (LS) was measured.Our results showed that: a) AcAc2 was found to be the most potent anticonvulsant ester, as it increased the LS of 574%, compared to controls; b) AcAc and AcAc2 administration caused a significant increase in tidal volume (VT) and thus minute ventilation c) while stabilizing respiratory frequency (fresp) between 15 min before and after seizure, compared to controls.We report that 1) KEs (notably AcAc and AcAc2) increase the animal's resistance to seizures, and 2) ventilation (VT and fresp) was significantly stimulated by the oral administration of KEs.

Supplemental ketone metabolic therapy slows tumor growth and increases survival time in mice with metastatic cancer

Metastasis is responsible for 90% of cancer‐related deaths in the U.S. Failure to test therapies in natural pre‐clinical models of metastasis has prevented the effective translation of treatments from lab to clinic. Metastatic cancer cells are highly glycolytic, requiring a large supply of glucose for energy. Mitochondrial dysfunction prevents cancer from efficiently using ketones for energy. Furthermore, ketones inhibit cancer cell proliferation in vitro. The metabolic deficiencies of cancer can be exploited with a ketogenic diet (KD) which lowers glucose and elevates ketones in the blood, a strategy that slows cancer progression in animals and humans. We hypothesized that elevating blood ketones with supplemental ketone administration (SKA) would inhibit cancer progression and enhance efficacy of the KD. We tested this metabolic therapy in the luciferase‐tagged VM‐M3 mouse model of metastatic cancer which spreads naturally in an immunocompetent host, mimicking the natural metastatic phenotype. Mice were fed either ketogenic or standard diet with supplemental ketones (1,3‐butanediol or ketone ester.) Tumor growth was monitored by in vivo bioluminescent imaging. SKA slowed tumor growth and increased survival time by 34–51% when delivered with standard or ketogenic diet. We propose that SKA could enhance the efficacy of standard care and improve the outcome of patients with advanced metastatic disease.Grant Funding Source: Office of Naval Research

A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) involves progressive accumulation of amyloid β-peptide (Aβ) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester–based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Aβ deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model.

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects

Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1–2h, reaching 3.30mM and 1.19mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8–3.1h for β-hydroxybutyrate and 8–14h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714mg/kg body weight, three times daily, over 5days (equivalent to 0.42, 1.07, and 2.14g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.

Development, testing and therapeutic applications of ketone esters (KE) for CNS oxygen toxicity (CNS‐OT); i.e., hyperbaric oxygen (HBO2)‐induced seizures

We previously described the effect of KEs, non‐ionized precursors of ketone bodies, in delaying seizures in rats breathing HBO2 at 5 ATA. We hypothesize that oral administration of specific KEs (esters of acetoacetate) will cause a rapid and sustained ketosis that confers neuroprotection against CNS‐OT in rats. Male rats (n = 53) were implanted with radio‐transmitters to measure diaphragmatic electromyogram (dEMG), ECG and EEG. ≥ 7 days post‐surgery, rats were fasted for 12h and administered intragastrically with 1 of 2 KEs (10g/kg), including R,S‐1,3‐butanediol acetoacetate monoester (mKE) or R,S‐1,3‐butanediol acetoacetate di‐ester (dKE) and placed into a hyperbaric chamber and pressurized to 5 ATA O2. Latency to seizure (LS) was measured from the beginning of maximum level of HBO2 until the onset of increased EEG activity and/or tonic‐clonic twitches. Blood was drawn from 18 animals and levels of glucose, pH, pO2, pCO2, β‐hydroxybutyrate, acetoacetate and acetone were analyzed. KEs caused a rapid and sustained ketosis and delayed LS by ~227% (mKE) and ~574% (dKE) compared to control (water). In conclusion, KEs mimic the mild therapeutic ketosis produced by ketogenic diets and confer a significant neuroprotective effect by delaying CNS‐OT (ONR).

Mitochondrial Biogenesis and Increased Uncoupling Protein 1 in Brown Adipose Tissue of Mice Fed a Ketone Ester Diet

We investigated the in vivo physiological responses to a diet in which D‐β‐hydroxybutyrate – (R)‐1,3 butanediol monoester (ketone ester, KE) replaced equicaloric amounts of carbohydrate in eight week old male C57BL/6J. The KE‐fed group had blood D‐β‐hydroxybutyrate (β HB) levels that were much greater than that achieved with high fat ketogenic diets. Voluntary food intake reduced dose‐dependently with KE in the diet. Feeding the KE diet for a month significantly increased the number of mitochondria, uncoupling protein 1 (UCP1), PPARγ, PGC‐1α as well as Sirt1 in the interscapular brown adipose tissue (IBAT). The KE group also had significantly greater 18F‐fluorodeoxyglucose (FDG) uptake in IBAT, indicating functional activation of the tissue. The ketone fed mice had greater plasma leptin levels and increased sympathetic nervous system activity to IBAT. KE‐fed mice exhibited elevated resting energy expenditure, but no difference in the total energy expenditure or body weight. The quantitative insulin‐sensitivity check index (QUICKI) was also significantly greater in the KE group. These results demonstrate KE as a potential anti‐obesity supplement.

ChemInform Abstract: Highly Enantioselective Synthesis of α‐Trifluoromethyldihydropyrans Using a Chiral Trifluoroethyl‐Substituted Thiourea Catalyst Derived from Amino Acid.

An enantioselective Michael addition of ethyl 4,4,4-trifluoro-3-oxobutanoate to α,β-unsaturated ketone esters using a chiral alkyl-substituted thiourea catalyst is reported. Excellent levels of stereo-induction (up to 98% ee) under mild reaction conditions were obtained to afford the corresponding α-trifluoromethyldihydropyrans.

Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

We measured the effects of a diet in which D-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [(18)F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.

Amine Synthesis through Mild Catalytic Hydrosilylation of Imines using Polymethylhydroxysiloxane and [RuCl2(arene)]2 Catalysts

Tolerate silicone! The stable [RuCl2(p-cymene]2 complex is an efficient catalyst for the direct chemoselective hydrosilylation of functionalized aldimines and ketimines into amines, using polymethylhydroxysiloxane as an inexpensive, stable, and safe hydrosilane source. The catalysis operates in ethanol, under air at room temperature, and tolerates the ketone ester and alkene functionality.

The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury

The pathological consequences of traumatic head injury result largely from the opening of the mitochondrial permeability transition pore (mPTP). The mPTP opens due to a decrease in brain phosphorylation energy resulting in a further decrease in brain ATP production and a measurable increase in brain heat generation and temperature. The increase in brain temperature can be measured transcranially by near infrared spectroscopy which can be used to diagnose traumatic brain injury (TBI) and to monitor treatment. Effective therapy of TBI can be achieved by closure of the mPTP by administration of cyclosporine A or by oral administration of ketone body esters. While ketosis has previously been known to prevent damage from TBI, the availability of oral ketone esters presents the first practical modality of achieving therapeutic levels of ketone bodies.

Synthesis of 3,4-fused cycloalkanopyrroles by 1,3-dipolar cycloaddition

The synthesis of a number of 3,4-fused cycloalkanopyrroles bearing substituents on the cycloalkane ring was accomplished by 1,3-dipolar cycloaddition. The yield of the cyclization appeared to depend on the base-sensitivity of the Michael acceptor, but the method is applicable across a broad range of cyclic α,β-unsaturated ketone esters. Functional group transformations can be undertaken following pyrrole synthesis to increase the diversity of cycloalkanopyrroles accessible by this method. One pyrrole thus made is a diester of a conformationally-constrained analogue of porphobilinogen, the precursor of the natural tetrapyrroles.

Highly Enantioselective Synthesis of α‐Trifluoromethyldihydropyrans Using a Chiral Trifluoroethyl‐substituted Thiourea Catalyst Derived from Amino Acid

AbstractAn enantioselective Michael addition of ethyl 4,4,4‐trifluoro‐3‐oxobutanoate to α,β‐unsaturated ketone esters using a chiral alkyl‐substituted thiourea catalyst is reported. Excellent levels of stereo‐induction (up to 98% ee) under mild reaction conditions were obtained to afford the corresponding α‐trifluoromethyldihydropyrans.

A Ketone Ester Diet Increases Brain Malonyl-CoA and Uncoupling Proteins 4 and 5 while Decreasing Food Intake in the Normal Wistar Rat

Three groups of male Wistar rats were pair fed NIH-31 diets for 14 days to which were added 30% of calories as corn starch, palm oil, or R-3-hydroxybutyrate-R-1,3-butanediol monoester (3HB-BD ester). On the 14th day, animal brains were removed by freeze-blowing, and brain metabolites measured. Animals fed the ketone ester diet had elevated mean blood ketone bodies of 3.5 mm and lowered plasma glucose, insulin, and leptin. Despite the decreased plasma leptin, feeding the ketone ester diet ad lib decreased voluntary food intake 2-fold for 6 days while brain malonyl-CoA was increased by about 25% in ketone-fed group but not in the palm oil fed group. Unlike the acute effects of ketone body metabolism in the perfused working heart, there was no increased reduction in brain free mitochondrial [NAD(+)]/[NADH] ratio nor in the free energy of ATP hydrolysis, which was compatible with the observed 1.5-fold increase in brain uncoupling proteins 4 and 5. Feeding ketone ester or palm oil supplemented diets decreased brain L-glutamate by 15-20% and GABA by about 34% supporting the view that fatty acids as well as ketone bodies can be metabolized by the brain.

ChemInform Abstract: 4-Quinolylmethyl and 1-Naphthylmethyl as Benzyl-Type Protecting Groups of Carboxylic Acids Removable by Homogeneous Palladium-Catalyzed Hydrogenolysis.

Abstract 4-Quinolylmethyl (4-QUI) esters are reduced by palladium-catalyzed hydrogenolysis by formate anion. The reaction conditions are compatible with reducible substituents or functional groups as aromatic bromo, alkene, aldehyde, ketone, nitrile, ethyl and benzyl esters. An allyl ester is cleaved selectively in the presence of a 4-QUI ester. 1-Naphthylmethyl (1-NAP) esters of α-amino acids could be deprotected without any racemization by the same methodology.

Efficient Synthesis of Substituted 2‐Amino‐3‐carbethoxythiophenes

A microwave‐assisted method for the synthesis of a variety of thiophene o‐aminoesters (2a–l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur.

Novel transformation of 2-substituted alkyl 1-indanone-2-acetates to 6-substituted 3,4-benzotropolones through sequential reduction and oxidation processes using Sm(II) and Ce(IV) salts

When 2-substituted alkyl 1-indanone-2-acetates 1 were treated with samarium diiodide, 3-substituted 2-hydroxy-2,3-methano-1-oxo-1,2,3,4-tetrahydronaphthalenes 4 were obtained. The reaction is proposed to proceed through a rearrangement initiated by intramolecular ketone–ester coupling. Oxidation of these products 4 or their silyl ethers 13 by ceric(IV) ammonium nitrate involving regioselective bond cleavage of their bicyclo[4.1.0]-rings produced the corresponding benzotropolone derivatives 10 .

Samarium Diiodide Promoted Intramolecular Ketone—Ester Coupling Reaction: Novel Cyclization and Ring Expansion Pathway.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dynamic kinetic resolution of racemic gamma-aryl-delta-oxoesters. Enantioselective synthesis of 3-arylpiperidines.

Cyclodehydration of racemic gamma-aryl-delta-oxoesters with (R)- or (S)-phenylglycinol stereoselectively affords bicyclic delta-lactams, in a process that involves a dynamic kinetic resolution. Subsequent reduction of these lactams leads to enantiopure 3-arylpiperidines. Starting from racemic aldehyde esters, this short sequence has been applied to the synthesis of (R)-3-phenylpiperidine and the antipsychotic drug (-)-3-PPP (an (S)-3-arylpiperidine), whereas starting from racemic ketone esters enantiopure cis-2-alkyl-3-arylpiperidines are prepared.

Samarium diiodide-promoted intramolecular ketone–ester coupling reaction: novel cyclization and ring expansion pathway

When ethyl 2-substituted-1-indanone-2-carboxylates were treated with samarium diiodide (SmI2), ring expansion products such as 3-substituted-1,2-naphthoquinones were isolated. Alcohols were also obtained as the mixture of cis- and trans-isomers of hydroxy and ester substituents. A reaction mechanism involving intramolecular addition of samarium ketyl radicals to ester substituents followed by ring expansion was proposed for the formation of the one-carbon homologated products. Similarly, reaction of ethyl 1-substituted-2-oxo-1-cyclopentanecarboxylates with SmI2 produced 3-substituted-2-hydroxy-2-cyclohexenones along with the corresponding alcohols.

Intramolecular and intermolecular ketone–ester reductive coupling reactions promoted by samarium(II) iodide

Intramolecular and intermolecular ketone–ester reductive coupling reactions promoted by SmI 2 have been studied. Substituted 2-hydroxy-5-ethoxycarbonylcyclopentanones, 5-ethoxycarbonylcyclopentenones and α-ketols were prepared in moderate to good yields at room temperature or under reflux under neutral conditions.