Stability studies of β-Amino- and β-Hydroxy difluoromethyl ketones in rat serum and rat liver microsomes.

Although difluoromethyl ketones are used as tools in chemical biology and leads in drug discovery, the metabolic stability of these compounds is generally uncharacterized and must be inferred from in vivo pharmacological assays. In order to address this gap which impedes their wider use, we have synthesized and performed metabolic stability studies for thirty-nine β-amino and β-hydroxy difluoromethyl ketones. These investigations provide structure-stability relationships of the difluoromethyl ketones following incubation with rodent serum and liver microsomes.

Synthesis of α,α-Difluoro-β-amino Ketones from -Boc-α-Amidosulfones and Pentafluoro--diols.

To circumvent the synthesis and isolation of imines, a method was devised to construct α,α-difluoro-β-amino ketones from -Boc-α-amidosulfones. The reactive nucleophiles, difluoroenolates, are generated in situ from the pentafluoro--diols using cesium fluoride in pyridine. NMR studies confirm the role of the α-amidosulfones in this process.

Transient Formation of Hemiketals from Pentafluoro--diols in the Presence of Alcohols.

Pentafluoro--diols have emerged as a source of reactive intermediates for synthesizing fluorinated molecules. When pentafluoro--diols were exposed to alcohols as solvents, the formation of transient hemiketals was detected by 19F NMR. The conversion rates to hemiketals were found to be higher with primary alcohols than with secondary or fluorinated alcohols.

Comparison of Conformational Analyses of Naturally Occurring Flavonoid--Glycosides with Unnatural Flavonoid-CF-Glycosides Using Molecular Modeling.

Many glycosylated natural products display biological activity and are deglycosylated by the metabolic processes of the body. Although unnatural CF-glycosides have been proposed as nonhydrolyzable analogues, CF-derivatives of natural products are exceedingly challenging to synthesize and few examples exist. These difluorinated molecules may have unique conformational behavior as a consequence of changing the glycosidic linkage.

Synthesis of Difluorinated Halohydrins by the Chemoselective Addition of Difluoroenolates to α-Haloketones.

α-Haloketones are valuable intermediates in the synthesis of pharmaceuticals and natural products because they display two electrophiles. Although chemoselective additions to each of these functional groups are known, the use of fluorinated nucleophiles has not been characterized, except for the dimerization of fluorohalomethyl ketones. Our studies demonstrate the use of difluoroenolates to create difluorinated bromohydrins and chlorohydrins from α-haloketones without any cyclization or rearrangement due to the mild conditions.

Synthesis, biological evaluation, and NMR studies of 3-fluorinated derivatives of 3',4',5'-trihydroxyflavone and 3',4',5'-trimethoxyflavone.

Flavones are valuable scaffolds in medicinal chemistry, especially as they display activity as antioxidants and neuroprotective agents. The need to incorporate a fluorine atom on flavones has driven much of the recent synthetic work in this area. We now report a route for the production of 3-fluorinated derivatives of 3',4',5'-trihydroxyflavone and 3',4',5'-trimethoxyflavone.

Synthesis of β-Fluoro-α,β-Unsaturated Amides from the Fragmentation of Morpholine 3,3,3-Trifluoropropanamide by Grignard Reagents.

Fluoroalkenes serve as bioisosteres to peptide bonds and are resistant to hydrolytic enzymes in vivo. Currently, α-fluoro-α,β-unsaturated carbonyl compounds are readily accessible via general synthetic methods; however, β-fluoro-α,β-unsaturated carbonyl groups are more challenging to construct. To address this need, we have designed a reagent, morpholine 3,3,3-trifluoropropanamide, that creates ()-β-fluoro-α,β-unsaturated amides upon the addition of many commonly used Grignard reagents.

Controlling the Cleavage of Carbon-Carbon Bonds To Generate α,α-Difluorobenzyl Carbanions for the Construction of Difluoromethylbenzenes.

Controlling the cleavage of carbon-carbon bonds during a chemical reaction is a substantial challenge; however, synthetic methods that accomplish this objective produce valuable and often unexplored reactivity. We have designed a mild process to generate α,α-difluorobenzyl carbanions in the presence of potassium carbonate by exploiting the cleavage of C-C bonds during the release of trifluoroacetate. The initiating reagent is potassium carbonate, which represents an improvement over existing protocols that require a strong base.

Agonists of the γ-aminobutyric acid type B (GABA) receptor derived from β-hydroxy and β-amino difluoromethyl ketones.

β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor.

Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines.

Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic structures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that unactivated imines will react with difluoroenolates under exceedingly mild conditions when using magnesium salts and organic bases. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-β-amino-carbonyl groups.

Conversion of Methyl Ketones and Methyl Sulfones into α-Deutero-α,α-Difluoromethyl Ketones and α-Deutero-α,α-Difluoromethyl Sulfones in Three Synthetic Steps.

Deuterodifluoromethyl ketones and sulfones were assembled in three synthetic steps from methyl ketones and sulfones, respectively. The key synthetic transformation is the deuteration of the difluorocarbanion generated by the release of trifluoroacetate from highly α-fluorinated gem-diols. High levels of deuterium on the "CFD" group were routinely observed.

Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement.

The success of fluorinated molecules in drug design has led medicinal chemists to search for new fluorine-containing substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiological conditions and displays unique physical and chemical properties.

Generation of Magnesium Pentafluoropropen-2-olate from Hexafluoroisopropanol and Synthesis of 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones.

2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones are valuable precursors to difluoroenolates following fragmentation during the release of trifluoroacetate; however, there are few synthetic strategies to prepare this unique class of compound. We addressed this issue and report a mild, two-step synthesis of 2,2,4,4,4-pentafluoro-3,3-dihydroxyketones from aldehydes. Specifically, aldehydes are treated with pentafluoropropen-2-olate, generated from a new fragmentation of hexafluoroisopropanol with a mixed Mg/Li amide, to give pentafluoroalcohols.

15-Methylene-Eburnamonine Kills Leukemic Stem Cells and Reduces Engraftment in a Humanized Bone Marrow Xenograft Mouse Model of Leukemia.

Recent studies suggest that leukemia stem cells (LSCs) play a critical role in the initiation, propagation, and relapse of leukemia. Herein we show that (-)-15-methylene-eburnamonine, a derivative of the alkaloid (-)-eburnamonine, is cytotoxic against acute and chronic lymphocytic leukemias (ALL and CLL) and acute myelogenous leukemia (AML). The agent also decreases primary LSC frequency in vitro.

Optimized Synthesis of a Pentafluoro--diol and Conversion to a -Glucopyranose through Trifluoroacetate-Release and Halogenation.

Pentafluoro--diols are substrates that enable the synthesis of valuable difluoromethylene-containing organic molecules through the release of trifluoroacetate. Currently, only one synthetic strategy is available to assemble these important precursors. Herein, two new synthetic strategies to a complex pentafluoro--diol are compared to the existing route, and an improved synthetic route has completed.

Energy Drinks: Implications for the Breastfeeding Mother.

Breastfeeding women may experience disrupted sleep schedules and be tempted to turn to popular energy drinks to reduce fatigue and enhance alertness, prompting the question: What are the maternal and child health implications for breastfeeding mothers consuming energy drinks? Caffeine and vitamin-rich energy drinks contain a variety of herbal ingredients and vitamins; however, ingredient amounts may not be clearly disclosed on product labels. Interactions between herbal ingredients and caffeine are understudied and not well defined in the literature. Some infants can be sensitive to caffeine and display increased irritability and sleep disturbances when exposed to caffeine from breastmilk.

In vitro characterization of transport and metabolism of the alkaloids: vincamine, vinpocetine and eburnamonine.

Purpose: Vincamine, vinpocetine and eburnamonine are alkaloids known for their neuroprotective attributes, enhancement of cerebrovascular blood flow and antitumor effect of their derivatives. However, the relative metabolic stability of these alkaloids and their extrusion by the drug efflux transporters expressed at the blood-brain barrier (BBB) are not clear. In this study, we developed rapid and sensitive methods for the detection of these alkaloids and investigated their relative metabolic stability and their interaction with drug efflux transporters.

Activation of the γ-Aminobutyric Acid Type B (GABA(B)) Receptor by Agonists and Positive Allosteric Modulators.

Since the discovery of the GABA(B) agonist and muscle relaxant baclofen, there have been substantial advancements in the development of compounds that activate the GABA(B) receptor as agonists or positive allosteric modulators. For the agonists, most of the existing structure-activity data apply to understanding the role of substituents on the backbone of GABA as well as replacing the carboxylic acid and amine groups. In the cases of the positive allosteric modulators, the allosteric binding site(s) and structure-activity relationships are less well-defined; however, multiple classes of molecules have been discovered.

Effect of Substituents and Stability of Transient Aluminum-Aminals in the Presence of Nucleophiles.

Disubstituted hydroxylamines were synthesized and used to form aluminum-amide complexes. These reagents masked carbonyl groups in situ from nucleophilic addition. The stability and utility of the aluminum-aminals are presented in the context of selectively controlling nucleophilic addition on substrates with multiple carbonyl groups.

Proposed actions for the US Food and Drug Administration to implement to minimize adverse effects associated with energy drink consumption.

Energy drink sales are expected to reach $52 billion by 2016. These products, often sold as dietary supplements, typically contain stimulants. The Dietary Supplement Protection Act claims an exemplary public health safety record.

A small molecule screen identifies a novel compound that induces a homeotic transformation in Hydra.

Developmental processes such as morphogenesis, patterning and differentiation are continuously active in the adult Hydra polyp. We carried out a small molecule screen to identify compounds that affect patterning in Hydra. We identified a novel molecule, DAC-2-25, that causes a homeotic transformation of body column into tentacle zone.