Synthesis and Biological Study of 4-Aminopyridine-Peptide Derivatives Designed for the Treatment of Neurodegenerative Disorders.

BACKGROUND: Alzheimer's disease (AD) and Multiple sclerosis (MS) lead to neurodegenerative processes negatively affecting millions of people worldwide. Their treatment is still difficult and practically incomplete. One of the most commonly used drugs against these neurodegenerative diseases is 4-aminopyridine. However, its use is confined by the high toxicity. OBJECTIVES: The aim of this work is to obtain new peptide derivatives of 4-aminopyridine with decreased toxicity compared to 4-aminopyridine. METHODS: Synthesis was conducted in solution using a consecutive condensation approach. The new derivatives were characterized by melting points, NMR, and Mass spectra. Important ADME (absorption, distribution, metabolism, and excretion) properties have been studied in silico using ACD/Percepta v.2020.2.0 software. Acute toxicity was determined in mice according to a Standard protocol. All new derivatives were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (NEURO 2A) tumor cell lines via a standard MTT-based colorimetric method. ß-secretase inhibitory activity was determined by applying the fluorescent method. RESULTS: New derivatives of 4-aminopyridine containing analogues of the ß-secretase inhibitory peptide (Boc-Val-Asn-Leu-Ala-OH) were obtained. The in vivo toxicity of the tested compounds was found to be as high as 1500 mg/kg. Cell toxicity screening against tumor cell lines of different origins showed negligible growth-inhibitory effects of all investigated 4-aminopyridine analogues. CONCLUSION: Synthesis of new peptide derivatives of 4-aminopyridine is reported. Acute toxicity studies revealed a ca. 150 times lower toxicity of the new compounds as compared to 4-aminopyridine that may be ascribed to their peptide fragment.

New Galantamine Derivatives with Inhibitory Effect on Acetylcholinesterase Activity.

BACKGROUND: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer's disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). OBJECTIVE: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. METHODS: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. RESULTS: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. CONCLUSION: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention.

Synthesis of New Galanthamine-Peptide Derivatives Designed for Prevention and Treatment of Alzheimer's Disease.

BACKGROUND: Although no effective treatment for the Alzheimer's disease currently exist, some drugs acting as Acetylcholinesterase inhibitors, like galanthamine have positively affected such patients. ß- and/or γ-secretase inhibitors are another type of potential drugs. Here we report synthesis of new peptide-galanthamine derivatives, with expected inhibitory activity against both Acetylcholinesterase and ß-secretase. OBJECTIVES: The aim of this work is obtaining new peptide derivatives of galanthamine with decreased toxicity compared to galanthamine. METHODS: Syntheses were conducted in solution using fragment condensation approach. The new derivatives were characterized by melting points, angle of optical rotation, NMR and Mass spectra. Acute toxicity was determined on mice, according to a Standard protocol. All new compounds were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (Neuro-2a) tumor cell lines via a standard MTT-based colorimetric method. RESULTS: New derivatives of galanthamine containing shortened analogues of ß-secretase inhibitor (Boc- Asn-Leu-Ala-Val-OH) and either nicotinic or isonicotinic residue, both connected with a linker (L-Asp) to position 11 of galanthamine were obtained. In vivo toxicity of some new compounds was found up to 1000 mg/kg. Cell toxicity screening against the tumor cell lines showed negligible growth-inhibiting properties of the galanthamine derivatives. CONCLUSION: Synthesis of new galanthamine derivatives comprising peptide moiety and nicotinic acid or isonicotinic acid is reported. Acute toxicity studies reveal they are about 100 times less toxic than galanthamine. This effect is due to the peptide fragment. Cytotoxicity studies show good correlation with low toxicity results. These results are encouraging for the application of this class compounds as medicines.

Monolayer formed by l-Asp-based gemini surfactants self-assembled in 1D nanostructures.

Herein, studies on the surface activities of newly synthesized l-Asp-based gemini surfactants, both nonionic and anionic, are presented. Conductometry, tensiometry, and the Langmuir-Blodgett (LB) film technique were applied for this purpose. π-A isotherms were obtained with a Langmuir trough and Wilhelmy balance. The structures of the monolayers assembled at the air/water interface and those deposited as LB films were studied via Brewster angle microscopy (BAM) and atomic force microscopy (AFM). The 2D films formed by the anion-active compounds show a well-known pattern of a monolayer film, whereas the nonionogenic amphiphiles have been found to be 1D structures with nano-widths and micro-lengths that align with each other during the process of compression; this is the first study where the organization of 1D fibrils in 2D films during compression is reported. The scanning electron microscopy (SEM) study reveals that 1D nanostructure formation is an intrinsic tendency of these molecules as not only nonionogenic surfactants, but also the anion active representatives have been constructed in the solid state by fibrillary structures.

Energy barrier for protein adhesion and crystal nucleation on flat alien substrates.

From the experimentally defined rate of heterogeneous formation of protein crystals and number of collisions between protein molecules with substrate, the energy barrier for adhesion of protein molecule to alien materials is estimated. According to the Boltzmann equation for energy distribution this barrier is of the order of 10(-12) erg per molecule.