Nanoparticles of water-soluble dyads based on amino acid fullerene C60 derivatives and pyropheophorbide: Synthesis, photophysical properties, and photodynamic activity.

Synthesis, spectral properties, and photodynamic activity of water-soluble amino acid fullerene C60 derivatives (AFD) and four original AFD-PPa dyads, obtained by covalent addition of dye pyropheophorbide (PPa) to AFD, were studied. In aqueous solution, these AFD-PPa dyads form nanoassociates as a result of self-assembly. In this case, a significant change in the absorption spectra and strong quenching of the dye fluorescence in the structure of the dyads were observed. A comparison of superoxide or singlet oxygen generation efficiency of the studied compounds in an aqueous solution showed the photodynamic mechanism switching from type II (singlet oxygen generation of the native dye) to I type (superoxide generation of dyads). All dyads have pronounced phototoxicity on cells Hela with IC50 9.2 µM, 9.2 µM, 12.2 µM for dyads Val-C60-PPa, Ala-C60-PPa and Pro-C60-PPa, respectively. Such facilitation of type I photodynamic mechanism could be perspective against hypoxic tumors.

[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 1, 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 nitroderivatives of fullerene C60 on amyloid fibrils of Abeta(1-42) peptide of the brain and muscle X-protein].

The antiamyloidogenic capacity of water-soluble nitroderivatives of fullerene C60: methyl ester of LN-[(2-nitroglyceryl) fullerenyl] proline, methyl ester of LN-[(2,3-dinitroglyceryl) fullerenyl] proline, and 2 nitroxyethyl ether LN-([2-(nitroxy) ethyl] fullerenyl) proline has been studied in vitro by high-resolution electron microscopy. It was shown that these fullerene C60 nitroderivatives are able to prevent the formation of amyloid fibrils by the brain Abeta(1-42)-peptide and muscle X-protein and to destroy mature fibrils. Electron microscopy is a promising method for selecting effective antiamyloidogenic drugs. The antiamyloidogenic activity of nanodimensional fullerene C60 nitroderivatives offers strong possibilities for creating a new nanotechnology for the therapy of amyloidoses.

[In vitro antiviral activity of fullerene amino acid derivatives in cytomegalovirus infection]. / Protivovirusnaia aktivnost' aminokislotnykh proizvodnykh fullerena pri tsitomegalovirusnoi infektsii in vitro.

The in vitro effect of 5 water soluble fullerene C60 amino acid derivatives (FAD) on the development of cytomegalovirus infection was studied in the schemes of the therapeutic, prophylactic and virucidal action. The following compounds as FAD were used: fullerene conjugated with Na salt of gamma-aminobutyric acid (C60-ABA-Na), 2 derivatives based on Na salts of fullerene-gamma-aminobutyric acid and fullerene-omega-caproic acid (C60-ABA-OH-Na and C60-ACA-OH-Na respectively) and 2 derivatives based on methyl ethers of the above mentioned fullerene amino acids (C60-ABA-OH-CH3 and C60-ACA-OH-CH3). All the FAD were able to inhibit the development of the virus cytopathogenic action in the cell culture. However, the compounds had different antiviral properties. C60-ABA-OH-Na, C60-ABA-CH3 and C60-ACA-CH3 showed marked antiviral activity in the prophylactic scheme. 50-Percent inhibition of the virus cytopathogenic action (ID50) was observed when concentrations of the compounds were 0.31, 5 and 25 mcg/ml respectively. C60-ACA-OH-Na inhibited the development of cytomegalovirus infection in the cell culture only in the scheme of the therapeutic action (ID50 4 mcg/ml). C60-ABA-Na had the highest antiviral effect. In a concentration of 0.22 mcg/ml it inhibited the cytomegalovirus plague-forming capacity by 50% in both the prophylactic and the virucidal schemes. The chemotherapeutic index of the compound was within the limits of 2500 to 5450.

[HIV reproduction inhibition by amino acid and dipeptide derivatives of fullerene C60]. / Ingibirovanie reproduktsii VICH s pomoshch'iu aminokislotnykh i dipeptidnykh proizvodnykh Fullerena C60.

Target-aimed synthesis of a new class of water soluble amino acid and dipeptide derivatives of fullurene (C60 - X) for inhibition of specific virus enzymes, i.e. protease and reverse transcriptase of HIV (P HIV and RT HIV) in cell culture lytic and chronic infections was performed. Out of 13 tested substances, 8 showed inhibitory activity and 5 were effective in pharmacological doses (ID50 varied within 0.46 to 1.0 mcm/ml with respect to the lytic infection and 5.0 to 12.5 mcm/ml with respect to the chronic infection). The activity of (1), (2), (6), (7) and (8) was comparable to that of azidothymidine, a nucleozide inhibitor of RT HIV in the cell culture lytic infection. The substances also showed marked virucidal action. The cytotoxicity (survival, antiproliferative effect) varied from low to very low with respect to the rapidly dividing cells MT4 and HTHIV27 (CD50 > 200-800) and was somewhat higher with respect to PBL (CD50 > 100). The selectivity index (SI = CD50/ID50) was equal to 165-2000 for various samples. The prototype derivatives (1) and (2) had a selective (competitive) inhibitory action on the recombinant protease of HIV with IC50 = 1.25-2.76 mcM, while derivatives (1), (la) and (2) had a noncompetitive inhibitory action on the recombinant reverse transcriptase of HIV (Ki = 7.9-12.1 mM). The pharmacokinetic study of the prototype derivative (1) on laboratory animals revealed no acute or chronic toxicity up to the terminal high concentrations. As for (1), its high interspecies (mice--rabbits) relative bioavailability equal to 110% was shown.

[Suppression of cytomegalovirus infection in cell system by fullerene amino acid derivates]. / Podavlenie tsitomegalovirusnoi infektsii v kletochnoi sisteme aminokislotnymi proizvodnymi fullerena.

Effects of two water-soluble derivatives of fullerene C60-o-aminocaproic acid (C60-ACA) and C60 sodium salt of omega-aminocaproic acid (C60-Na-ACA) on in vitro cytomegalovirus (CMV) infection were studied. C60-Na-ACA 4-5-fold inhibited the cytopathic effect of CMV in comparison with C60-ACA, the effective dose for C60-Na-ACA being 0.6 microgram/ml and that for C60-ACA 2.7 micrograms/ml. Immunocytochemical analysis of virus proteins in infected cells has shown that C60-Na-ACA inhibits the production of late structural CMV protein gB, but does not modify the expression of immediate early nonstructural protein IEp72. Studies of cell viability, growth characteristics, and DNA synthesis revealed that the cytotoxic effect of C60-Na-ACA on human diploid fibroblasts in negligible, the cytotoxicity index varying from 160 to 1500 micrograms/ml in different tests. Selectivity index for C60-Na-ACA is 267-2500, which differs negligibly from that of gancyclovir (100-1000), while the cytotoxicity of C60-Na-ACA is essentially lower.

[Structure formation of water insoluble fullerene amino acid derivatives in organic solvents]. / Strukturoobrazovanie vodonerastvorimykh aminokislotnykh proizvondykh fullerena v organicheskikh rastvoriteliakh.

The time-dependent structure formation of the fullerene derivative of p-amino benzoic acid in organic solvents was studied by scanning electron microscopy. It was shown that, during storage of solutions, the structures are destroyed.

Membranotropic properties of the water soluble amino acid and peptide derivatives of fullerene C60.

The modifying effects of the products of the equimolar addition Of DL-alanine and DL-alanyl-DL-alanine to fullerene C60 on the structure and permeability of the lipid bilayer of phosphatidylcholine liposomes has been studied using the luminescence probe technique. It is shown that these water soluble amino acid and dipeptide derivatives of fullerene (C60-AD) are quenchers of pyrene fluorescence and erythrosine phosphorescence of in both a water solution and liposomes. To study the permeability of the lipid bilayer a procedure based on the triplet probe technique has been developed. It has been found that the C60-AD derivatives under study are able to localize inside the artificial membrane, to penetrate into the liposomes through the lipid bilayer and to perform activated transmembrane transport of bivalent metal ions.