Rivastigmine structure-based hybrids as potential multi-target anti-Alzheimer's drug candidates.

In recent years, an increasing amount of work has been carried out regarding the study of the etiopathology of Alzheimer's Disease (AD). This neurodegenerative disease is characterized by several organic and molecular correlates, which paint a complex picture that also reflects the historic challenge faced by the worldwide scientific community in finding an effective cure for it. In this paper, we describe the synthesis of novel rivastigmine derivatives and their characterization as wide-spectrum enzyme (AChE, BChE, FAAH, MAO-A and MAO-B) inhibitors with potential application in the therapy of AD following the paradigm of multi-target design.

A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake.

Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution.

-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of -CE-123 and -modafinil. To address this objective, a precise liquid chromatography-high resolution mass spectrometry method was developed and partially validated.

Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat.

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory.

Quantification of atropine sulphate monohydrate and obidoxime dichloride in two-chamber autoinjectors for accessing uniformity of dosage.

In the treatment of organophosphate poisoning atropine sulphate monohydrate (AT) and obidoxime dichloride (OB) play a vital role. Currently, the Austrian Armed Forces use the DOUBLEPEN OA two-chamber autoinjector (ChemProtect) to administer these two drugs. The autoinjector is a part of military standard equipment as a "Basic CBRN-First Aid Kit" and contains OB and AT with a declared concentration of 220 mg/2 ml and 2 mg/2 ml, respectively.

A Novel and Selective Dopamine Transporter Inhibitor, -MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.

Biosynthetic Potential of the Endophytic Fungus Helotiales sp. BL73 Revealed via Compound Identification and Genome Mining.

Endophytic fungi have been recognized as prolific producers of chemically diverse secondary metabolites. In this work, we describe a new representative of the order Helotiales isolated from the medicinal plant Bergenia pacumbis. Several bioactive secondary metabolites were produced by this Helotiales sp.

Cognitive profiling and proteomic analysis of the modafinil analogue S-CE-123 in experienced aged rats.

The lack of novel cognitive enhancer drugs in the clinic highlights the prediction problems of animal assays. The objective of the current study was to test a putative cognitive enhancer in a rodent cognitive test system with improved translational validity and clinical predictivity. Cognitive profiling was complemented with post mortem proteomic analysis.

Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition.

Endophytic sp. LN303 from Edelweiss Produces Emestrin and Two New 2-Hydroxy-4 Pyridone Alkaloids.

In the search for new antibiotics, several fungal endophytes were isolated from the medicinal plant subsp. (Edelweiss). The extract from one of these fungi classified as sp.

Actaea racemosa L. extract inhibits steroid sulfation in human breast cancer cells: Effects on androgen formation.

Background: Actaea racemosa L., also known as black cohosh, is a popular herb commonly used for the treatment of menopausal symptoms. Because of its purported estrogenic activity, black cohosh root extract (BCE) may trigger breast cancer growth.

Developments of Smart Drug-Delivery Systems Based on Magnetic Molecularly Imprinted Polymers for Targeted Cancer Therapy: A Short Review.

Cancer therapy is still a huge challenge, as especially chemotherapy shows several drawbacks like low specificity to tumor cells, rapid elimination of drugs, high toxicity and lack of aqueous solubility. The combination of molecular imprinting technology with magnetic nanoparticles provides a new class of smart hybrids, i.e.

Differences in Hypothalamic Lipid Profiles of Young and Aged Male Rats With Impaired and Unimpaired Spatial Cognitive Abilities and Memory.

Lipids play a major role for several brain functions, including cognition and memory. There is a series of work on individual lipids showing involvement in memory mechanisms, a concise lipidome was not reported so far. Moreover, there is no evidence for age-related memory decline and there is only work on brain of young vs.

Metabolism of Estrogens: Turnover Differs Between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells.

High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases.

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships.

The Novel Atypical Dopamine Uptake Inhibitor -CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding.

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options.

Resveratrol Inhibits Key Steps of Steroid Metabolism in a Human Estrogen-Receptor Positive Breast Cancer Model: Impact on Cellular Proliferation.

The role of resveratrol (RES) in preventing breast cancer is controversial, as low concentrations may stimulate the proliferation of estrogen-receptor alpha positive (ERα+) breast cancer cells. As metabolism is the key factor in altering cellular estrogens, thereby influencing breast tumor growth, we investigated the effects of RES on the formation of estrogen metabolites, namely 4-androstene-3,17-dione (AD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone-3--sulfate (DHEA-S), estrone (E1), estrone-3-sulfate (E1-S), 17β-estradiol (E2), 17β-estradiol-3--(β-D-glucuronide) (E2-G), 17β-estradiol-3--sulfate (E2-S), 16α-hydroxy-17β-estradiol (estriol, E3), and testosterone (T) in ERα- MDA-MB-231 and ERα+ MCF-7 cells. Incubation of both of the cell lines with the hormone precursors DHEA and E1 revealed that sulfation and glucuronidation were preferred metabolic pathways for DHEA, E1 and E2 in MCF-7 cells, compared with in MDA-MB-231 cells, as the V values were significantly higher (DHEA-S: 2873.

A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats.

Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task.

Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered.

The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A Targeted Metabolomics Approach.

The beneficial effect of dietary soy food intake, especially for women diagnosed with breast cancer, is controversial, as data has shown that the soy isoflavones genistein and daidzein may even stimulate the proliferation of estrogen-receptor alpha positive (ERα+) breast cancer cells at low concentrations. As genistein and daidzein are known to inhibit key enzymes in the steroid metabolism pathway, and thus may influence levels of active estrogens, we investigated the impacts of genistein and daidzein on the formation of estrogen metabolites, namely 17β-estradiol (E2), 17β-estradiol-3-(β-D-glucuronide) (E2-G), 17β-estradiol-3-sulfate (E2-S) and estrone-3-sulfate (E1-S) in estrogen-dependent ERα+ MCF-7 cells. We found that both isoflavones were potent inhibitors of E1 and E2 sulfation (85-95% inhibition at 10 μM), but impeded E2 glucuronidation to a lesser extent (55-60% inhibition at 10 μM).

Recent advancements on the use of 2-methyltetrahydrofuran in organometallic chemistry.

Abstract: Since the introduction of 2-methyltetrahydrofuran as an useful alternative to the classical tetrahydrofuran, there has been a continuous interest in the synthetic community operating at academic and industrial towards it. In particular, the much higher stability that basic organometallic reagents display in 2-methyltetrahydrofuran makes it suitable for processes involving such sensitive species including asymmetric transformations. The easy formation of an azeotropic mixture with water, the substantial immiscibility with water, and the fact it derives from natural sources (corncobs or bagasse), allow to consider it in agreement with the Anastas' Geen Chemistry principles.

A detailed proteomic profiling of plasma membrane from zebrafish brain.

Zebrafish (Danio rerio) is a well-established model organism in developmental biology and disease modeling. In recent years, an increasing amount of studies used zebrafish to analyze the genetic changes underlying various neurological disorders. The brain plasma membrane proteome represents the major subsets of signaling proteins and promising drug targets, but is often understudied due to traditional experimental difficulties including problems with solubility, detergent removal, or low abundance.

Biomimetic strategies for sensing biological species.

The starting point of modern biosensing was the application of actual biological species for recognition. Increasing understanding of the principles underlying such recognition (and biofunctionality in general), however, has triggered a dynamic field in chemistry and materials sciences that aims at joining the best of two worlds by combining concepts derived from nature with the processability of manmade materials, e.g.