G. N. Bogdanov

Study of the neuroprotective action of hybrid structures based on fullerene C60

The neuroprotective action of hybrid structures based on fullerene C60 with attached proline amino acid has been studied. Hybrid structures contained natural antioxidant carnosine or addends with one or two nitrate groups. It has been shown that all studied compounds had antioxidant activity and decreased the concentration of malondialdehyde in homogenates of the rat brain. Compound I, which contained the antioxidant carnosine, has been found to be the most effective antioxidant. All compounds except IV and V inhibited the activity of monoamine oxidase B, while compounds I–IV increased the activity of monoamine oxidase A. All investigated compounds inhibited glutamate-induced Ca2+ uptake into synaptosomes of the rat brain cortex. Compound III, containing two nitrate groups, has been found to be the most effective inhibitor. This compound caused a significant increase of the currents of AMPA receptors (AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid).

Effect of nitroxyalkyl derivatives of fullerenylproline on the activity of CA3+-ATPase of sarcoplasmic reticulum

The effect of nitroxyalkyl derivatives of fullerenylproline methyl ester on the enzymatic activity of Ca2+-ATPase of sarcoplasmic reticulum (SR) has been studied. It is shown that hybrid derivatives of C60 fullerene are capable of inhibiting the activity of Ca2+-ATPase of SR. The mononitrate inhibits the hydrolytic activity of the enzyme with Kiu2009=u20091.92u2009×u200910−6xa0M; active Ca2+ transport, with Kiu2009=u20093.79u2009×u200910−6xa0M. The dinitrate inhibits ATP hydrolysis with Kiu2009=u20092.38u2009×u200910−8xa0M; Ca2+ transport, with Kiu2009=u20093.08u2009×u200910−8xa0M. Fullerenylproline methyl ester does not affect the enzymatic activity of Ca2+-ATPase. Based on these data it is possible to predict the possible fields of application for hybrid fullerene derivatives as potential drugs.

Hydroxamic acids: synthesis and adjuvant activity in combinatorial anticancer therapy

Monoand disubstituted N-hydroxyamides of dicarboxylic acids were prepared by reaction of dicarboxylic acids or acid anhydrides with hydroxylamine. The use of these compounds in combinatorial cytostatic therapy of implanted tumors with cisplatin or cyclophosphamide totally inhibits metastasis formation in B16 melanoma and Lewis lung carcinoma, and resulted in 100% survival of leukemic animals.

Effect of lipophilicity of C60 fullerene derivatives on their ability to inhibit peroxide oxidation of lipids in aqueous medium

The aqueous solutions of C60 fullerene derivatives were studied by means of dynamic light scattering, their effect on the peroxide oxidation of lipids (POL) in aqueous solutions was investigated via chemiluminescence method. It was shown that the colloidal solubility in water, which defines the antioxidant activity of C60 fullerene derivatives during POL, is controlled by the chemical structure of the addend added to C60 fullerene. For the studied derivatives, the direct dependence of the efficiency of POL inhibition on the lipophilicity was established.

Luminescent techniques in investigation of the biological properties of fullerene-based hybrid nanostructures

It has been shown that amino acid derivatives of C60 fullerene (ADFs) are effective quenchers of phosphorescence of the triplet probes eosin and erythrosine. The rate constants of erythrosine phosphorescence quenching by ADFs in aqueous solutions and model membranes have been determined. Using the triplet probe technique, the ability of ADFs to be transported across the lipid bilayer into the inner space of liposomes have been revealed. By monitoring a change in the fluorescence intensity of a luminescent hybrid structure based on C60-proline and eosin, the distribution of the hybrid structure in animal organs was established. The stability of hybrid structures subjected to various chemical and biological impacts was studied by recording the fluorescence of a Gd@C82-based hybrid structure.

Bioantioxidants as inhibitors of aldehyde reductase

An analysis o f features o f the appearance and development of diabetic angiopathy shows that the pathogenesis is usually based on the production o f free-radical intermediates related to the molecular oxygen reduction, activation o f the lipid peroxidation, and modification o f the antioxidant cell status. These processes are initiated by the side reactions o f electron transfer from free-radical forms of coenzymes to oxygen, involved in the activation o f metabolic processes with the participation o f oxidoreductases, in particular, aldehyde reductase (AR) a key enzyme o f the sorbitol pathway [l 3 ] . An increase in the AR activity leads to the intensive conversion o f glucose into sorbitol. The latter is accumulated in the vessel walls, leading to the development o f degenerativesclerotic changes in the vessels and the appearance o f a diabetic cataract, retinopathy, or nephroand neuropathy [3]. There is some evidence that AR inhibitors can prevent the development o f these complications [4, 5]. Taking into account the existing notions that AR belongs to the membrane-bound enzymes and its activity is determined by the structural-functional state o f the biomembranes, it was of interest to study the behavior o f antioxidants as potential AR inhibitors. I f the antioxidants would exhibit a high inhibition activity with respect to AR, it will be possible to create promising drug preparations on this basis for the prophylaxis and therapy of complications involved in diabetes mellitus [6]. In this work we studied six antioxidants with different mechanisms of action. The group includes mexidol and emoxypin (3-hydroxypyridine derivatives whose protective antioxidant properties are based on interactions with singlet oxygen), carnosine (a dipeptide capable of deactivating lipid peroxides), phenosane and anphene (spatially-constrained phenols binding peroxide radicals), and TEMPO (a free nitroxyl radical capable o f trapping the R type radicals).

Synthesis of oxalic acid derivatives and their antitumor activity in experiments in vivo

A series of amino acid derivatives of oxalic acid were obtained. In combination therapy with conventional cytostatics used in lower doses, the new compounds substantially increase the efficacy of the drugs in the treatment of experimental P388 murine leukemia and some its drug-resistant strains.

Synthesis and antiischemic activity of dicarboxylic nitroxyalkylamides and nitroxyalkylimides

A number of dicarboxylic N-(2-nitroxyalkyl)amides and N-(2-nitroxyalkyl)imides were synthesized and their antiischemic activity was studied. The ratio of the areas of necrotic and ischemic zones was used as a criterion for evaluation of antiischemic activity. The maximum values were close to antiischemic activity of Nicorandil, with acute toxicity of compounds synthesized being considerably lower.

Nicotinic acid nitroxyalkylamides as NA/K-ATPase inhibitors

The inhibitory action of nicotinamide N-nitroxyalkylamide derivatives (NANDs) on the hydrolase activity of Na/K-ATPase was studied. NANDs contain two peptide bonds and fragments of amides of glycine, β-alanine, α-aminopropanecarboxylic acid, or γ-aminobutyric acid. It is established that the inhibitory effect of NANDs depends on the concentration and hydrophobicity. An increase in the hydrophobicity of NANDs is accompanied by a decrease in their inhibitory action. The most active inhibitor among the studied NANDs is N-nitroxyethylnicotinamide, which noncompetitively and reversibly interacts with Na/K-ATPase with Kiu2009=u20092.13 × 10–4 M.

Creation of a donor-acceptor pair for studying intraprotein electron transfer with the participation of amino-acid derivatives of fullerene C60

Efficient quenching of eosin phosphorescence by amino-acid derivatives of fullerene (AADFs) such as C60-alanine and C60-glycine in aqueous solutions indicates the possibility of transferring electrons from eosin to fullerene upon collisions or in the exciplex state. To investigate electron transfer in the protein structure, we studied the process of incorporation of C60-alanine and C60-glycine into the heme pocket of myoglobin by controlling Förster quenching. The dissociation constant for the protein-AADF complex was estimated.