Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzene thymidine mimics, some related alpha-anomers, and their evaluation as antiviral and anticancer agents

A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzenes having a variety of C-5 substituents (H, Me, F, Cl, Br, I, CF3, CN, NO2, NH2), designed as thymidine mimics, were synthesized for evaluation as anticancer and antiviral agents. The coupling reaction of 3,5-bis-O-(p-chlorobenzoyl)-2-deoxy-alpha-D-ribofuranosyl chloride with an organocadmium reagent [(2,4-difluorophenyl)2Cd] afforded a mixture of the alpha- and beta-anomeric products (alpha:beta = 3:1 to 10:1 ratio). Treatment of the alpha-anomer with BF3.Et2O in nitroethane at 110-120 degrees C for 30 min was developed as an efficient method for epimerization of the major alpha-anomer to the desired beta-anomer. The 5-substituted (H, Me, Cl, I, NH2) beta-anomers exhibited negligible cytotoxicity in a MTT assay (CC50 = 10(-3)-10(-4) M range), relative to thymidine (CC50 = 10(-3)-10(-5) M range), against a variety of cancer cell lines. In contrast, the 5-NO2 derivative was more cytotoxic (CC50 = 10(-5)-10(-6) M range). A number of 5-substituted beta-anomers, and some related alpha-anomers, that were evaluated using a wide variety of antiviral assay systems [HSV-1, HSV-2, varicella-zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV) and human immunodeficiency (HIV-1, HIV-2) viruses], showed that this class of unnatural C-aryl nucleoside mimics are inactive antiviral agents.     

Modulation of plant resistance to diseases by water-soluble chitosan

Low-molecular-weight water-soluble chitosan with a molecular weight of 5 kDa obtained after enzymatic hydrolysis of native crab chitosan was shown to display an elicitor activity by inducing the local and systemic resistance of Solanumi tuberosum potato and Lycopesicon esculentum tomato to Phytophthora infestans and nematodes, respectively. Chitosan induced the accumulation of phytoalexins in tissues of host plants, decreased the total content and changed the composition of free sterols producing adverse effects on infesters, activated chitinases, beta-glucanases, and lipoxygenases, and stimulated the generation of reactive oxygen species. The activation of protective mechanisms in plant tissues inhibited the growth of taxonomically different pathogens (parasitic fungus Phytophthora infestans and root knot nematode Meloidogyne incognita).     

Effect of initial (spontaneous) arterial pressure on systemic hemodynamic orthostatic responses

In anesthetized rats, a reverse linear correlation of arterial pressure (AP) shifts was found within the range of initial AP over 95 mm Hg under the head-up tilts at 30 and 45 degrees. Within the range beneath 95 mm Hg this correlation was transformed into the direct one. Under 60 degrees tilt such correlation only occurred within the range beneath 95 mm Hg. The direction and degree of the arterial system responsiveness seems to depend on the tilt value as well as on the range of the initial AP.     

Analysis of DNA status in bone marrow cells of mice internally irradiated with 90Sr

The response of bone marrow cells of CBA mice injected with 22.2, 222 and 592 kBq/animal to additional gamma-irradiation (3 Gy) for testing purposes was evaluated using SCG (Comet assay). A decrease in induction of DNA damage right after additional gamma-irradiation was determined. It correlated with bone marrow cell quantity and the tail length before additional gamma-irradiation. The results support the suggestion about the activation of DNA repair in bone marrow cells under exposure to 90Sr in vivo.     

ATP stimulates chemically sensitive and sensitizes mechanically sensitive afferents

We examined whether ATP stimulation of P2X purinoceptors would raise blood pressure in decerebrate cats. Femoral arterial injection of the P2X receptor agonist alpha,beta-methylene ATP into the blood supply of the triceps surae muscle induced a dose-dependent increase in arterial blood pressure. The maximal increase in mean arterial pressure (MAP) evoked by 0.1, 0.2, and 0.5 mM alpha,beta-methylene ATP (0.5 ml/min injection rate) was 6.2 +/- 2.5, 22.5 +/- 4.4, and 35.2 +/- 3.9 mmHg, respectively. The P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (2 mM ia) attenuated the increase in MAP elicited by intra-arterial alpha,beta-methylene ATP (0.5 mM), whereas the P2Y receptor antagonist reactive blue 2 (2 mM ia) did not affect the MAP response to alpha,beta-methylene ATP. In a second group of experiments, we tested the hypothesis that ATP acting through P2X receptors would sensitize muscle afferents and, thereby, augment the blood pressure response to muscle stretch. Two kilograms of muscle stretch evoked a 26.5 +/- 4.3 mmHg increase in MAP. This MAP response was enhanced when 2 mM ATP or 0.1 mM alpha,beta-methylene ATP (0.5 ml/min) was arterially infused 10 min before muscle stretch. Furthermore, this effect of ATP on the pressor response to stretch was attenuated by 2 mM pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (P < 0.05) but not by the P1 purinoceptor antagonist 8-(p-sulfophenyl)-theophylline (2 mM). These data indicate that activation of ATP-sensitive P2X receptors evokes a skeletal muscle afferent-mediated pressor response and that ATP at relatively low doses enhances the muscle pressor response to stretch via engagement of P2X receptors.