D. V. Mishchenko

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).

The effect of ascorbic acid on the efficiency of cytotoxic therapy with cytostatic drugs in combination with NaNO3 and hydroxamic acids

The present investigation is based on the paradoxical dichotomy of the biological action of nitric oxide (NO). Depending on its concentration in the organism, it can have therapeutic or pathogenic effect. It was shown that during the treatment with cisplatin (cPt) or cyclophospamide (CP), adjunct therapy with ascorbic acid (AA) known to increase the NO content in the organism extended the average lifespan (ALS) by 20—30% as compared to cytostatic monotherapy. Combination of cytostatics with sodium nitrate extended ALS by 20—38% depending on the concentration of the nitrate. The efficiency of cytotoxic therapy in combination with two chemo sensitizers (NaNO3 and hydroxamic acid) also depends on the concentration of injected NaNO3. Addition of AA to these combinations extended ALS by 16%, or inhibited it by 40%. Variation of the dose of injected NaNO3 that is a NO donor in combination with endogenous NO stimulated with AA controls the action of cytostatics and combinations thereof.

Effect of Cyclic Hydroxamic Acids Derived from Glycine and D,L-Alanine on Activity of Ca2+, Mg2+-ATPase Hydrolases of Sarcoplasmic Reticulum and Cyclic Guanosine Monophosphate Phosphodiesterase

The effects of cyclic hydroxamic acids (CHAs) derived from glycine and D,L-alanine on the enzymatic activity of Ca2+,Mg2+-ATPase from sarcoplasmic reticulum (Ca2+,Mg2+-ATPase SR) and cyclic guanosine monophosphate phosphodiesterase (PDEcGMP) were investigated. CHAs I (C5H10N2O2), II (C6H12N2O2), III (C8H15N3O2), IV (C9H17N3O2), V (C11H21N3O2), and VI (C12H23N3O2) were modulators of Ca2+,Mg2+-ATPase SR enzyme activity. Compounds I-VI decoupled to various extents the hydrolytic and transport functions of Ca2+,Mg2+-ATPase SR, disrupting the ratio of intra- and extracellular Ca2+ ions. This affected the adhesion of metastatic cells to capillary endothelium. Compounds IV and VI had the highest metastasis inhibition indices (MII%) for B-16 melanoma of 33 and 81%, respectively. This correlated with a decreased Ca2+ transmembrane transfer coefficient into SR vesicles of 0.75 for IV and 0.5 for VI compared with a [Ca2+]/[ATP] ratio in the control of 1.4. CHAs I-VI did not affect the functioning of PDEcGMP. The results enabled potential antimetastatic drugs in the CHA series to be predicted.

Design of a hybrid nanostructure based on fullerene C60 and biologically active substance for modeling physiological properties of compounds

The effects of cognitive-stimulating substance BD-2 of the γ-carboline family and a hybrid compound based on fullerene C60 and attached BD-2 on various aspects of the behavior of animals were studied. The synthesized hybrid fullerene compound (HFC) has no side psychostimulating effect characteristic of BD-2 but fully retains the properties of a cognitive-stimulating agent. The design of hybrid compounds based on fullerene C60 and pharmacologically active groups can be one of the ways for optimizing therapeutically promising compounds.

Ways to enhance chemosensitizing of tumor cells with NO donors in tumor therapy with cytostatics and hydroxamic acids

The influence of an organic NO donor belonging to non-steroidal anti-inflammatory drugs (NSAIDs) — NO-indomethacin (NO-Ind) on the antitumor effect of cyclophosphamide (CP) and its compositions with asparagyl hydroxamic acid (AHA) were studied, along with the influence on the activity of cytochrome P-450. Compared to a previously studied NSAID — diclofenac hydroxamic acid nitrate — NO-Ind exhibited lower enhancement of CP activity even when hydroxamic acid was added to the drug composition. EPR spectroscopy was used to evaluate the changes in activity of P-450 under the action of modified NSAIDs. The studies demonstrated partial inhibition of cytochrome P-450, the inhibition time is being greater for the first NSAID than for NO-Ind. The duration of P-450 inhibition under the action of different NO donors influences activity of CP.

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.

Sulfur-containing phenolic antioxidants increasing antitumor efficiency of cyclophosphamide and its combination with nitric oxide donor

Due to the multifactorial nature of cancer diseases, investigations of combinations of the known cytostatics with substances that are chemosensitizers and act on various molecular target in the organism gain increasing significance. Polyfunctional compounds, whose molecules contain several reaction centers, serve as resources improving the efficiency of the chemosensitizing effect of various substances for chemotherapy by cytostatic agents. Classical representatives of such polyfunctional substances are sulfur-containing derivatives of alkylated phenols, the high oxidation activity of which is determined by a combination of the antiradical activity of the phenol fragments with the antiperoxide activity of the sulfur-containing groups. It is shown that the sulfur-containing phenolic antioxidant sodium S-[3-(3-tert-butyl-4-hydroxyphenyl) propyl] thiosulfate (TC-13) has no antitumor activity but enhances chemotherapeutic activity of cytostatic cyclophosphamide taken in a subtherapeutic dose, increasing the index of average life span of mice with leukemia P388 from 196 to 283%. In addition, a combination of TC-13 with the nitric oxide donor (NaNO2) increases the antitumor activity of cytostatic cyclophosphamide by 110% for the same experimental model of mice at 50% survived animals.

Effect of Mexidol and Nitroxymexidol on Phosphodiesterase Activity, Some Oxidation Processes, and Hypoxia Resistance

The effect of mexidol (M) and nitroxymexidol (NM) on the activity of phosphodiesterase of cyclic guanosine monophosphate (PDEcGMP), regulation of lipid peroxidation (LPO), and antiradical and antihypoxic activity was investigated under normoxia and normobaric hypercapnic hypoxia conditions. Reversible and noncompetitive inhibition of the hydrolytic function of PDEcGMP by M and NM was revealed. The Ki value for M was 1 ×10–4 M; for NM, 1 ×10–5 M, i.e., NM was 10 times more active than M. It was shown that the lifetime of experimental animals in a closed space increased by 36% under the action of M as compared with that of the control group while it increased by 53% for NM. The ventricular contraction time increased by 137% for NM. The atrial contraction time increased from 31 min in the control to 52 and 57 min for M and NM, respectively.

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 Ki = 2.13 × 10–4 M.