Synthesis of (−)‐DAPD

A new synthesis of (?)‐DAPD, suitable for large scale development, is described.     

In vivo and in silico anti-inflammatory mechanism of action of the semisynthetic (−)-cubebin derivatives (−)-hinokinin and (−)-O-benzylcubebin

(?)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (?)-hinokinin (HK) and (?)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween® 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 – cyclooxygenase-2) interaction in comparison with CUB and HK.     

Metabolism of (−)-deprenyl and PF-(−)-deprenyl in brain after central and peripheral administration

We examined the cerebral metabolism of L-deprenyl and its fluoro-derivative pF-deprenyl, assaying the parent compounds, their metabolites desmethyl deprenyl, L-amphetamine, and L-methamphetamine, and the fluoro analogs of these metabolites. We compared the levels of the metabolites after subcutaneous injection with those after intracerebral administration (via microdialysis) of the parent compounds. The assay of the parent compounds and their metabolites was by GC-MS measurement of the components of brain microdialysate samples. After their subcutaneous administration, deprenyl and F-deprenyl rapidly entered the brain and then their concentration decreased, with an approximate half-life of 4.5 h. After the intracerebral administration the diffusion from the site of administration was minor. A small fraction (a few percent) of the intracerebrally administered deprenyl was metabolized in situ in the brain possibly by a nonenzymatic process. Metabolism of pF-deprenyl was somewhat more rapid. The higher cerebral levels of metabolites after the subcutaneous administration indicate their exogenous origin—metabolism of parent compounds in the periphery and penetration of the brain by the metabolites.     

Biological activities of (−)-epicatechin and (−)-epicatechin-containing foods: Focus on cardiovascular and neuropsychological health

Recent studies have suggested that certain (?)-epicatechin-containing foods have a blood pressure-lowering capacity. The mechanisms underlying (?)-epicatechin action may help prevent oxidative damage and endothelial dysfunction, which have both been associated with hypertension and certain brain disorders. Moreover, (?)-epicatechin has been shown to modify metabolic profile, blood's rheological properties, and to cross the blood-brain barrier. Thus, (?)-epicatechin causes multiple actions that may provide unique synergy beneficial for cardiovascular and neuropsychological health. This review summarises the current knowledge on the biological actions of (?)-epicatechin, related to cardiovascular and brain functions, which may play a remarkable role in human health and longevity.     

Production of d(−)-lactate from sucrose and molasses

Escherichia coli W3110 derivatives, strains SZ63 and SZ85, were previously engineered to produce optically pure D(-) and L(+)-lactate from hexose and pentose sugars. To expand the substrate range, a cluster of sucrose genes (cscR' cscA cscKB) was cloned and characterized from E. coli KO11. The resulting plasmid was functionally expressed in SZ63 but was unstable in SZ85. Over 500 mM D(-)-lactate was produced from sucrose and from molasses by SZ63(pLOI3501).     

Promotion of Neuronal Plasticity by (−)-Epigallocatechin-3-Gallate

The consumption of (−)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound found in green tea, has been associated with various neurological benefits including cognitive improvement. The physiological basis for this effect is unknown. In this study, we used synaptic transmission between the CA3 and CA1 regions (Schaffer collateral) of the mouse hippocampus to examine the effects of EGCG on neuronal plasticity. We found that the level of high frequency stimulation-evoked long-term potentiation (LTP) was significantly enhanced when hippocampal slices were pre-incubated with 10 μM EGCG for 1 h prior to the experiment. EGCG incubation also enabled hippocampal slices prepared from Ts65Dn mice, a Down syndrome mouse model deficient in LTP, to express LTP to a level comparable to the normal controls. EGCG treatment did not alter the degree of pair-pulse inhibition; therefore, the enhancement effect of EGCG is unlikely to involve the attenuation of this inhibitory mechanism.     

Identification and characterization of a novel (−)-vibo-quercitol 1-dehydrogenase from Burkholderia terrae suitable for production of (−)-vibo-quercitol from 2-deoxy-scyllo-inosose

Applied Microbiology and Biotechnology - (−)-vibo-Quercitol is a deoxyinositol (1l-1,2,4/3,5-cyclohexanepentol) that naturally occurs in oak species, honeydew honey, wines aged in oak...     

Microbial Hydroxylation of (−)-α-Santonin by Aspergillus niger

The microbiological transformation of a sesquiterpene lactone, (−)-α-santonin was carried out by using Aspergillus niger MIL 5024 and MIL 5025. Strain MIL 5024 brings about the transformation of (−)-α-santonin (400 mg) to 11-hydroxy-(−)-α-santonin (P1) (50.4 mg), 3,6,9-trihydroxy-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (P2) (22.4 mg), and 3,6-dihydroxy-9,10-seco-selina-1,3,5(10)-trien-9,12-dioic acid-12,6-lactone (P3) (27.1 mg), which were isolated and characterized by UV, IR, mass and ¹H-NMR spectroanalyses. All of these products are described for the first time. Results similar to those with MIL 5024 were also obtained from the transformation of (−)-α-santonin by the other isolate, strain MIL 5025.     

Isolation and characterization of rat intestinal bacteria involved in biotransformation of (−)-epigallocatechin

Two intestinal bacterial strains MT4s-5 and MT42 involved in the degradation of (?)-epigallocatechin (EGC) were isolated from rat feces. Strain MT4s-5 was tentatively identified as Adlercreutzia equolifaciens. This strain converted EGC into not only 1-(3, 4, 5-trihydroxyphenyl)-3-(2, 4, 6-trihydroxyphenyl)propan-2-ol (1), but also 1-(3, 5-dihydroxyphenyl)-3-(2, 4, 6-trihydroxyphenyl)propan-2-ol (2), and 4′-dehydroxylated EGC (7). Type strain (JCM 9979) of Eggerthella lenta was also found to convert EGC into 1. Strain MT42 was identified as Flavonifractor plautii and converted 1 into 4-hydroxy-5-(3, 4, 5-trihydroxyphenyl)valeric acid (3) and 5-(3, 4, 5-trihydroxyphenyl)-γ-valerolactone (4) simultaneously. Strain MT42 also converted 2 into 4-hydroxy-5-(3, 5-dihydroxyphenyl)valeric acid (5), and 5-(3, 5-dihydroxyphenyl)-γ-valerolactone (6). Furthermore, F. plautii strains ATCC 29863 and ATCC 49531 were found to catalyze the same reactions as strain MT42. Interestingly, formation of 2 from EGC by strain MT4s-5 occurred rapidly in the presence of hydrogen supplied by syntrophic bacteria. Strain JCM 9979 also formed 2 in the presence of the hydrogen or formate. Strain MT4s-5 converted 1, 3, and 4 to 2, 5, and 6, respectively, and the conversion was stimulated by hydrogen, whereas strain JCM 9979 could catalyze the conversion only in the presence of hydrogen or formate. On the basis of the above results together with previous reports, the principal metabolic pathway of EGC and EGCg by catechin-degrading bacteria in gut tract is proposed.     

Complexation of aluminium with (−) -epigallocathechin gallate studied by spectrophotometry

Complexation equilibria between Al(III) and (−)-epigallocathechin gallate (EGCG) in the presence of acetate buffer have been studied by spectrophotometry. The method is based on the competition between EGCG and buffer ligands for Al(III) ions. The apparent formation constant of the EGCG complex for Al(III), which could be determined by measuring the absorbance of the free EGCG, decreased with increasing acetate ion concentration at a fixed pH. This phenomenon has been quantitatively investigated and both types of complexes (EGCG and acetate) could be analyzed. The apparent formation constant of Al(III) complex with EGCG also decreased with decreasing pH at a fixed acetate ion concentration. The pH dependence of the apparent formation constant indicates the 1:1 competition between metal ions and hydrogen ions for the binding site of EGCG. The intrinsic formation constant of Al-EGCG complex, the proton association constant of EGCG and the formation constant of Al-acetate complex are found to be log K_Al-EGCG = 7.6 ± 0.1, log K_H-EGCG = 7.65 ± 0.03 and log K_Al-acetate = 2.07 ± 0.05 by a graphical analysis.     

Effects of (−)-epicatechin and derivatives on nitric oxide mediated induction of mitochondrial proteins

Impaired mitochondrial function represents an early manifestation of endothelial dysfunction and likely contributes to the development of cardiovascular diseases (CVD). The stimulation of mitochondrial function and/or biogenesis is seen as a means to improve the bioenergetic and metabolic status of cells and thus, reduce CVD. In this study we examined the capacity of the flavanol (?)-epicatechin and two novel derivatives to enhance mitochondrial function and protein levels in cultured bovine coronary artery endothelial cells. As nitric oxide production by endothelial cells is suspected in mediating mitochondria effects (including biogenesis), we also examined the dependence of responses on this molecule using an inhibitor of nitric oxide synthase. Results indicate that the flavanol (?)-epicatechin and derivatives are capable of stimulating mitochondrial function as assessed by citrate synthase activity as well as induction of structural (porin, mitofilin) and oxidative phosporylation protein levels (complex I and II). Effects were blocked by the use of the chemical inhibitor of the synthase thus, evidencing a role for nitric oxide in mediating these effects. The results observed indicate that the three agents are effective in enhancing mitochondria function and protein content. The effects noted for (?)-epicatechin may serve to explain the healthy effects on cardiometabolic risk ascribed to the consumption of cocoa products.     

Occurrence of l-(−)-Pipecolic Acid in the Culture Medium of Rumen Ciliate Protozoa

Effect of phenoxazine derivatives (actinomycin D, l,8-dimethyl-3-aminophenoxazone-2, 3-aminophenoxazone-2, sodium resazurate, gallocyanine, fluorescent blue and capri blue) on amino acid transport in rat small intestine was investigated using tissue accumulation method. Capri blue (CI–51015) inhibited the accumulation of l-leucine, l-alanine and l-valine, and scarcely inhibited that of D-glucose. Kinetic analysis showed that the inhibition of amino acid accumulation by this pigment was non-competitive. Actinomycin D had no effect on amino acids and d-glucose accumulation in vitro at the high and low concentrations of these substances. High concentration of actinomycin D and long period of incubation had no effect, too. Accumulation of amino acids into the intestinal tissue was not significantly decreased or increased by the presence of other phenoxazine derivatives.     

Synthesis and neuropharmacological evaluation of esters of R(−)-N-alkyl-11-hydroxy-2-methoxynoraporphines

We synthesized several esters of R(?)-N-alkyl-11-hydroxy-2-methoxynoraporphines, assessed their affinities at dopamine D₁ and D₂ receptors in rat forebrain tissue and quantified their effects on motor activity in normal adult male rats. Tested compounds displayed moderate to high affinities to D₂ receptors but low affinities to D₁ receptors. The most D₂-potent (K_i = 18.9 nM) and selective novel agent (>529-fold vs D₁ sites) was R(?)-2-methoxy-11-acetyloxy-N-n-propylnoraporphine (compound 4b). At moderate doses, the compound proved to have prolonged behavioral locomotor activity.     

Effects of (−)-Sesamin on Chronic Stress-Induced Anxiety Disorders in Mice

This study investigated the effects of (?)-sesamin on chronic electric footshock (EF) stress-induced anxiety disorders in mice. Mice were treated with (?)-sesamin (25 and 50 mg/kg) orally once a day for 21 days prior to exposure to EF stress (0.6 mA, 1 s every 5 s, 3 min). Mice treated with (?)-sesamin (25 and 50 mg/kg) exhibited less severe decreases in the number of open arm entries and time spent on open arms in the elevated plus-maze test and the distance traveled in the open field test following exposure to chronic EF stress. Similarly, mice treated with (?)-sesamin exhibited significantly less severe decreases in brain levels of dopamine, norepinephrine, and serotonin following exposure to chronic EF stress. Increases in serum levels of corticosterone and expression of c-Fos were also less pronounced in mice treated with (?)-sesamin (25 and 50 mg/kg). These results suggest that (?)-sesamin may protect against the effects of chronic EF stress-induced anxiety disorders by modulating dopamine, norepinephrine, and serotonin levels, c-Fos expression, and corticosterone levels.     

Pharmacophore-based design and discovery of (−)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer’s disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (?)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC₅₀ 31.6?nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ₄₂) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP₆₉₅ cells at 50?µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.     

Biotransformation of (−)-epicatechin, (+)-epicatechin, (−)-catechin,and (+)-catechin by intestinal bacteria involved in isoflavone metabolism

Isoflavone-metabolizing bacteria, Adlercreutzia equolifaciens, Asaccharobacter celatus, Slackia equolifaciens, and Slackia isoflavoniconvertens catalyzed C-ring cleavage of (–)-epicatechin and (+)-catechin, (+)-epicatechin, and (–)-catechin in varying degrees. The cleaving abilities of (–)-epicatechin and (+)-catechin were enhanced by hydrogen, except (+)-catechin cleavage by S. equolifaciens, which was not accelerated. (?)-Catechin cleavage by Ad. equolifaciens was remarkably accelerated by hydrogen.     

(−)-5,6-Dehydrocamphor from the antifungal essential oil of Zuccagnia punctata

The essential oils from aerial parts of nine populations of Zuccagnia punctata Cav. (Fabaceae) were obtained by hydrodistillation and analyzed by GC–FID, GC–MS and ¹³C NMR. A total of 80 constituents, mainly oxygenated monoterpenes, were identified representing from 79.0 to 95.2% of the total oils which showed different composition patterns. The unusual compound (?)-5,6-dehydrocamphor, the major constituent in six of the samples investigated with percentages ranging from 12.3% to 56.5%, was isolated for the first time from nature and its structure was completely defined from NMR spectrometric data. Microscope studies of leaves indicated that not only capitate glands but also non-glandular trichomes, not previously described in this species, were present on the leaf surfaces.The essential oil showed antifungal activity against the dermatophytes Microsporum gypseum, Tricophyton rubrum and T. mentagrophytes with MIC values between 15.6 and 125 μg ml^?1, being T. rubrum the most susceptible species.