Search

Conjugates of phosphorylated dideoxynucleoside antiviral drugs dideoxycytidine (zalcitabine) and lamivudine with SiO2 nanoparticles were obtained via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry between a nucleoside triphosphate containing an alkynyl group at the γ-phosphate or azidothymidine triphosphate and SiO2 nanoparticles containing alkyl azide or alkynyl groups, respectively. 4-(Prop-2-yn-1-yloxy)butylamino group has been attached to the γ-phosphate group of dideoxycytidine (zalcitabine) and lamivudine 5'-triphosphates via the phosphoramidate linkage. New compounds were shown to be potent killers of human colon carcinoma cells. Anti-HIV activity of the conjugates was demonstrated as well. The conjugates of phosphorylated lamivudine and dideoxycytidine (zalcitabine) showed higher potency than the parent nucleosides. The conjugate of phosphorylated azidothymidine was less active against HIV-1 than the parent nucleoside probably because of the replacement of its 3'-azido group by 1,2,3-triazole ring. These results show an opportunity for using SiO2 nanoparticles as a transport for delivering phosphorylated nucleosides to cells in order to increase their efficiency as antiviral and anticancer drugs.

Tetrapyrrolic macrocycles are suitable for a variety of chemical modifications aimed at new agents for binary antitumor treatment and diagnosis. Previously we have reported that the conjugation of one single carborane cage to the chlorin e6 macrocycle, a modification designed for tumor sensitization in photodynamic (PDT) and boron neutron capture (BNCT) therapies, yielded the derivative with a higher photosensitizing potency in the models of transplanted rodent tumors. This effect was mechanistically linked to the localization of the carboranylchlorin in membrane organelles due to the carborane moiety. Further exploring the potential of modified tetrapyrrolic compounds as photoradiosensitizers we synthesized the chlorin derivative carrying four closo-carborane cages (44 boron atoms) and 16 fluorine atoms at the periphery of the macrocycle (fluorinated tetracarboranylchlorin, compound 1). For comparison of the properties of 1, its fluorine free congener (tetracarboranylchlorin 6) was obtained. The water soluble 1 and 6 accumulated preferentially in cells selected for resistance to chemotherapeutic drugs (multidrug resistance and cisplatin resistance) than in the parental non-selected counterparts. Compounds 1 and 6 showed a negligible dark cytotoxicity. In contrast, a monochromatic light illumination of cells loaded with low micromolar concentrations of 1 or 6 triggered rapid (within minutes) photonecrosis as determined by the entry of propidium iodide or SYTOX dyes into the parental as well as into resistant cells. In vivo 1 or 6 (up to 80 mg/kg i.p.) caused no general toxicity in Balb/c or C57BL6 mice. Illumination with a monochromatic light of B16 melanoma transplants in mice injected with 5 mg/kg 1 or 6 caused a significant shrinkage of tumor foci, with no re-growth in 77.8% animals by day 21 post PDT. BNCT on C6 rat glioma xenografts in Balb/c nu/nu mice injected i.p. with 5 mg/kg 1 led to a decrease of tumor foci and cure of animals by day 29 whereas the radiosensitizing potency of 6 was less pronounced. This difference was attributable to a limited intratumoral accumulation of 6. Altogether, an extensive modification of the chlorin macrocycle periphery with polyfluorines and polycarboranes yielded potent and well tolerable compounds for PDT and BNCT.

Experimental investigation of hexachlorocyclopentadiene [4+2]-cycloaddition to 2-substituted 4,7-dihydro-1,3-dioxepins revealed an atypical stereochemical effect. Clear experimental evidence was obtained that more bulky C2 substituents favour the thermodynamically and sterically less favourable endo -isomers. The possible reasons for such behaviour are secondary interactions of the highest occupied and lowest unoccupied orbitals in the transition state for endo- cycloaddition, diastereotopic solvation and coordination of the attacking diene reagent to the acetal oxygens. The reaction stereoselectivity also depends on the solvent nature and reaction temperature. We have also found that microwave irradiation significantly influences the [4+2]-cycloaddition yields and stereochemistry, though the nature of the underlying effects remains unclear.

The maleimide moiety is widely used in drug design. To explore the properties of maleimide containing photosensitizers we obtained a series of new β-maleimide functionalized meso-arylporphyrins through acylation of β-amino group in porphyrins with maleic anhydride followed by condensation of maleic acid monoamides. The selective reactivity of porphyrin maleimides toward thiols was demonstrated using mercaptocarboranes and cysteine. New derivatives retained the ability of tetrapyrrolic macrocyclic compounds to absorb light in visible spectral region and to generate triplet states and reactive oxygen species upon photoactivation. Importantly, illumination of cells loaded with a cell permeable 2-{3-[(o-carboran-1′-yl)thio]pyrrolidine-2,5-dione-1-yl}-5,10,15,20-tetraphenylporphyrin triggered rapid (within the initial minutes) generation of superoxide anion radical concomitantly with a decrease of mitochondrial membrane potential, and then the loss of the plasma membrane integrity and cell death. Thus, the maleimide-substituted porphyrins represent a new chemotype of polyfunctionalized compounds for an in-depth investigation as photosensitizers in cancer and beyond.

The important role in the maintenance of redox homeostasis is played by the ratio of ROS generation and catabolism catalyzed by enzymes whose imbalance can lead to an increase in the intracellular level of ROS and the development of some pathologies including cancer. Here we studied expression of genes, which involve in the control of the cellular redox state, under the development of resistance of human ovarian carcinoma SKOV-3 cell to cisplatin; its cytostatic effect is associated in a great part with prooxidant effect. It was found that the formation of cancer cell resistance was accompanied by an increase in the expression of genes encoding key antioxidant enzymes (SOD2, CAT, GPX1, HO-1) in parallel with a significant decrease in expression of the NOX5 gene, which controls one of major sources of ROS. The coordinated character of changes in the expression of genes can be promoted by enhanced expression of transcription factor Nrf2 in addition with the growth of GSH/GSSG ratio. The obtained results testify to the redox-dependent development of the adaptive antioxidant response as an important process in the mechanism of formation of cancer cell resistance to cisplatin. Acknowledgements: The publication was prepared with the support of the “RUDN University Program 5–100”.

Aims Here we studied the expression of isoforms of redox-dependent antioxidant enzymes and a rise of adaptive antioxidant response under development of cancer cells resistance to anticancer agent cisplatin (CDDP) possessed pro-oxidant action. Results Under development of resistance of human erythroleukemia K562 and ovarian carcinoma SKOV-3 cells to CDDP co-ordinative enhanced expression of genes encoding isoforms of superoxide dismutase (SOD1, SOD2), glutathione peroxidase (GPx1, GPx4), glutathione transferase (GSTP1-1, GSTМ1-1), glutaredoxin (GLRX1, GLRX2), thioredoxin (TRX1,TRX2) was found in both types of resistant cells in compare with wild cells. In addition, growth of GSH/GSSG ratio as index of cellular redox state as well as elevated level of transcription factor Nrf2 were observed in resistant K562/DOX and SKVLB cells. Decrease of apoptotic cell death was observed under exposure to hydrogen peroxide in the CDDP-resistant cells possessed elevated antioxidant status, as evidenced by low generation of ROS. It can be concluded that the mechanism of the formation of cancer cells resistance to CDDP involves the development of adaptive antioxidant response as key in stress adaptation.