Pavel N. Solyev

Synthesis and Anti‐HIV Properties of New Carbamate Prodrugs of AZT

A series of new 5′‐O‐carbamate prodrugs of AZT have been prepared. The stability in biological media, anti‐HIV properties and pharmacokinetic parameters in dogs were evaluated. The compounds display moderate anti‐HIV activity in cell culture. After oral administration of carbamate IV in dogs, both intact prodrug IV and released AZT were discovered in dog blood. Pharmacokinetic parameters of the compound IV were estimated. Half‐life (T1/2) of AZT released after oral administration of IV in dogs was close to that after administration of AZT itself, and time to the maximum concentration (Tmax) of AZT released from IV was two and three times longer compared with that of AZT and H‐phosphonate AZT, respectively. Acute toxicity was more than five times less if compared with AZT. As a result, we consider this series of carbamate derivatives of AZT as perspective for development of anti‐HIV agents.

5′-Phosphonate Derivatives of 2′,3′-Dideoxy-3′-Thiacytidine as New Anti-HIV Prodrugs

Two new phosphonate 3TC prodrugs were synthesized and studied in MT‐4 cells as inhibitors of HIV replication. Their pharmacokinetic parameters were evaluated following intragastric administration in rabbits and oral administration in dogs. Both compounds were much less toxic than parent 3TC in cell cultures and could generate the active nucleoside in laboratory animals.

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

The hepatitis C virus (HCV) causes chronic liver disease leading to fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection triggers various types of cell death which contribute to hepatitis C pathogenesis. However, much is still unknown about the impact of viral proteins on them. Here we present the results of simultaneous immunocytochemical analysis of markers of apoptosis, autophagy, and necrosis in Huh7.5 cells expressing individual HCV proteins or their combinations, or harboring the virus replicon. Stable replication of the full-length HCV genome or transient expression of its core, Е1/Е2, NS3 and NS5B led to the death of 20–47% cells, 72 h posttransfection, whereas the expression of the NS4A/B, NS5A or NS3-NS5B polyprotein did not affect cell viability. HCV proteins caused different impacts on the activation of caspases-3, -8 and -9 and on DNA fragmentation. The structural core and E1/E2 proteins promoted apoptosis, whereas non-structural NS4A/B, NS5A, NS5B suppressed apoptosis by blocking various members of the caspase cascade. The majority of HCV proteins also enhanced autophagy, while NS5A also induced necrosis. As a result, the death of Huh7.5 cells expressing the HCV core was induced via apoptosis, the cells expressing NS3 and NS5B via autophagy-associated death, and the cells expressing E1/E2 glycoproteins or harboring HCV the replicon via both apoptosis and autophagy.

Conjugates of 17-substituted testosterone and epitestosterone with pyropheophorbide a differing in the length of linkers

Graphical abstract Figure. No Caption available. HighlightsTestosterone and epitestosterone chemically conjugated with pyropheophorbide a.Spectral properties and molecular models of conjugates are presented.Epitestosterone conjugates inhibit LNCaP and PC‐3 cells growth stronger.Conformationally rigid conjugates possess stronger anti‐proliferative activity. ABSTRACT Conjugates of 17&agr;‐substituted testosterone (1 and 2) and 17&bgr;‐substituted epitestosterone (3 and 4) with pyropheophorbide a were synthesized. The scheme consisted of synthesis of 17&agr;‐hydroxy‐3‐oxopregn‐4‐en‐21‐oic and 17&bgr;‐hydroxy‐3‐oxopregn‐4‐en‐21‐oic acids, and their coupling with pyropheophorbide a by means of either ethylene diamine, or 1,5‐diamino pentane linkers. Mutual influence of steroidal and macrocyclic fragments in conjugates molecules was dependent on configuration of C17 and length of linker, that was established by analysis of 1H NMR spectra and molecular models of conjugates. Studies of interaction of conjugates with prostate carcinoma cells revealed that their uptake and internalization were independent on the androgen receptor activity, but dependent on the structure of conjugates, decreasing in the following row: 3 > 4 ≥ 1 > 2. Conjugates significantly decreased the LNCaP and PC‐3 cells growth at 96 h incubation. Epitestosterone derivatives 3 and 4 also showed superior anti‐proliferative activity versus testosterone ones. Conformationally more rigid conjugates 1 and 3, comprising short linkers, were more active than those with long linkers; conjugate 3 was the most potent.

Novel 5′-Norcarbocyclic Derivatives of Bicyclic Pyrrolo- and Furano[2,3-d]Pyrimidine Nucleosides

Here we report the synthesis and biological activity of new 5′-norcarbocyclic derivatives of bicyclic pyrrolo- and furano[2,3-d]pyrimidines with different substituents in the heterocyclic ring. Lead compound 3i, containing 6-pentylphenyl substituent, displays inhibitory activity with respect to a number of tumor cells with a moderate selectivity index value. Compound 3i induces cell death by the apoptosis pathway with the dissipation of mitochondrial potential.

Aerobic Co or Cu/NHPI-catalyzed oxidation of hydride siloxanes: synthesis of siloxanols

A highly efficient preparative method for the synthesis of siloxanols based on aerobic Co(OAc)2 or Cu(OAc)2/NHPI-catalyzed oxidation of hydride siloxanes using “green”, commercially available, simple inexpensive reagents and mild reaction conditions has been proposed. This is a general reaction for the synthesis of mono-, oligo- and polymeric siloxanols with various structures (linear, branched and cyclic).

Synthesis of Cytokinins via Enzymatic Arsenolysis of Purine Nucleosides

This unit describes an effective method for the preparation of natural cytokinins and their synthetic derivatives based on enzymatic cleavage of the N‐glycosidic bond of N6‐substituted adenosine or O6‐substituted inosine derivatives in the presence of purine nucleoside phosphorylase (PNP) and Na2HAsO4. The arsenolysis reaction is irreversible due to the hydrolysis of the resulting α‐D‐ribose‐1‐arsenate. As a result, the desired products are formed in near‐quantitative yields, as indicated by high‐performance liquid chromatography (HPLC) analysis, and can easily be isolated. In the strategy used here, the ribose residue acts as a protective group.

4-Chloro-l-kynurenine as fluorescent amino acid in natural peptides

Abstract4-Chloro-l-kynurenine (3-(4-chloroanthraniloyl)-l-alanine, l-4-ClKyn), an amino acid known as a prospective antidepressant, was recently for the first time found in nature in the lipopeptide antibiotic taromycin. Here, we report another instance of its identification in a natural product: 4-chloro-l-kynurenine was isolated from acidic hydrolysis of a new complex peptide antibiotic INA-5812. l-4-ClKyn is a fluorescent compound responsible for the fluorescence of the above antibiotic. Whereas fluorescence of 4-chlorokynurenine was not reported before, we synthesized the racemic compound and studied its emission in various solvents. Next, we prepared conjugates of dl-4-ClKyn with two suitable energy acceptors, BODIPY FL and 3-(phenylethynyl)perylene (PEPe), and studied fluorescence of the derivatives. 4-Chloro-dl-kynurenine emission is not detected in both conjugates, thus evidencing effective energy transfer. However, BODIPY FL emission in the conjugate is substantially reduced, probably due to collisional or photoinduced charge-transfer-mediated quenching. The intrinsic fluorescence of l-4-ClKyn amino acid in antibiotics paves the way for spectral studies of their mode of action.

Optimized synthesis of 3′-O-aminothymidine and evaluation of its oxime derivative as an anti-HIV agent

Abstract The synthesis and isolation of 3′-O-aminothymidine oximes have been optimized. Synthesized compounds were characterized by NMR and UV spectral and analytical data. A mixture of previously not reported syn and anti isomers of acetaldoximes was assessed for anti-HIV activity and the prevention of syncytia formation caused by HIV-1 infection.

New Dinucleoside Phosphonate Derivatives as Prodrugs of 3′-Azido-3′-Deoxythymidine and β-L-2′,3′-Dideoxy-3′-Thiacytidine: Synthesis and Anti-HIV Properties

New phosphonate homodimers of 3′-azido-3′-deoxythymidine (AZT) and a phosphonate heterodimer of β-L-2′,3′-dideoxy-3′-thiacytidine (3TC) and AZT were synthesized. The compounds demonstrated moderate anti-HIV activity. Stability of the compounds in human blood serum was studied. A correlation between anti-HIV activity and stability was defined.