Synthesis and biological activity of some new 5'-O-acyl tiazofurin derivatives.

Three new 5'-O-acyl tiazofurin derivatives 2-4 were synthesized and evaluated for their antiproliferative activity against different tumour cell lines as well as for their ability to induce apoptosis in C6 cells in vitro. Apart of the antitumour assays, the cell membrane permeation of 2-4 and their intracellular metabolism in C6 cells in vitro was also studied in order to evaluate their potential as possible tiazofurin bioisosteres or prodrugs.

Combination of nucleoside analogues tiazofurin and ribavirin downregulates experimental autoimmune encephalomyelitis.

The effect of combined treatment with ribavirin and tiazofurin on the development of experimental autoimmune encephalomyelitis, the best characterized animal model for human autoimmune disease multiple sclerosis, was investigated. The disease was induced in highly susceptible Dark Agouti rats with spinal cord homogenate in complete Freund's adjuvant. Although ribavirin or tiazofurin alone reduced the clinical and histopathological signs of experimental autoimmune encephalomyelitis, the combination of drugs achieved the same effect with significantly lower doses.

Synthesis, X-ray crystal structures and biological activity of 16-amino-17-substituted-D-homo steroid derivatives.

D-Homo derivatives in the androstane and estrane series, 12-19, were synthesized by a fragmentation-cyclization reaction of 16-oximino-17-hydroxy-17-substituted derivatives 3-9, or by cyclization of the corresponding D-seco derivatives 20-26. The structures were confirmed by X-ray analysis of compounds 12 and 16. Preliminary assessment of inhibitory effects of D-homo derivatives from androstane series towards aromatase, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17 alpha-hydroxylase/C17-20 lyase (P450c17) and 17 beta-HSD indicated much lower inhibitory potential compared to previously tested activity of another type of D-modified steroids, namely D-seco derivatives. Also, assessment of potential antiestrogenic activity of derivatives from estrane series showed absence of such an activity.

Sulfinosine-induced cell growth inhibition and apoptosis in human lung carcinomas in vitro.

In spite of tremendous effort for improved therapy, lung cancer remains the leading cause of cancer-related deaths worldwide. In the present study, we used the novel purine ribunocleoside sulfinosine and evaluated its antiproliferative and apoptotic outcome on the non-small cell lung carcinoma cell line (NSCLC) and the small cell lung carcinoma cell line (SCLC). Using a BrdU incorporation-test sulfinosine inhibited cell growth in a dose dependent-manner. ID50 values were 4.65 +/- 0.17 microM in the case of NSCLC cells, and 3.59 +/- 0.81 microM in the case of SCLC cells. MTT testing revealed that IC50 values were 6.24 +/- 0.77 microM for NSCLC and 5.68 +/- 0.58 microM for SCLC. Inhibitory concentrations (IC50 and ID50) for sulfinosine were nonsignificantly lower in SCLC cells compared to NSCLC cells, indicating similar susceptibility of the cells. Flow-cytometric analysis, TUNEL staining, DNA laddering and cell death ELISA test were used to investigate apoptotic cell death. Our results demonstrated that high concentrations of sulfinosine can cause typical DNA laddering, a hallmark for apoptosis. Evidence of free nucleosomes and enzymatic labeling of fragmented DNA confirmed apoptosis involvement in sulfinosine cytotoxicity. In addition, flow-cytometric analysis showed that 25 microM sulfinosine arrested cell cycle progression at the G2M phase and induction of apoptosis in both cell lines. From these results, we concluded that sulfinosine may act as an anticancer agent and further studies may prove its efficacy in lung cancer cells. Thus the biological effects of sulfinosine may be due to modulation of cell growth, cell death, and cell cycle regulatory molecules.

D-Secoestrone derivatives. VI. 17 beta-Benzyl-17 alpha-hydroxy-3-methoxyestra-1,3,5(10)-trien-16-one.

The title molecule, C(26)H(30)O(3), shows a novel chemical rearrangement of the substituents at position 17, i.e. an alpha-orientation of the hydroxy group and a beta-orientation of the bulky benzyl moiety. The packing arrangement consists of coils formed by O(2)...O(3) hydrogen bonds along the c axis. The compound shows complete loss of oestrogenic activity, and neither does it exhibit an antagonistic effect.

Ribavirin reduces clinical signs and pathological changes of experimental autoimmune encephalomyelitis in Dark Agouti rats.

The effect of ribavirin on development of experimental autoimmune encephalomyelitis (EAE) was investigated. The disease was induced in genetically susceptible Dark Agouti rats with syngeneic spinal cord homogenate in complete Freund's adjuvant (SCH-CFA). Depending on the amount of mycobacteria in CFA, the animals developed either moderate or severe EAE. Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was applied i.p. at a daily dosage of 30 mg/kg in two treatment protocols: from the start of immunization (preventive treatment) or from the onset of the first EAE signs after the induction (therapeutic treatment). Signs of EAE began between 7 and 9 days after induction and peaked at days 11-13. In moderate EAE (mean maximal severity score 3.33 +/- 0.21), the recovery was completed by days 23-26, whereas, in severe EAE (mean maximal severity score 4.5 +/- 0.23), obvious recovery was not detected. Preventive ribavirin treatment significantly decreased clinical signs after both moderate (score 1.75 +/- 0.25, P < 0.05) and severe (score 3.62 +/- 0.31, P < 0.015) immunization. Also, disease manifestations were reduced by therapeutic treatment of ribavirin (mean maximal severity score 2.5 +/- 0.2 vs. 3.33 +/- 0.21 in controls, P < 0.005) but less so in comparison with preventive treatment. Analysis of the effects of ribavirin on histopathologic changes in the spinal cord tissue revealed a reduction of mononuclear cell infiltrates, composed of T cells and macrophages/microglia, and the absence of demyelination, which were pronounced in control EAE animals. Beneficial effects of preventive and therapeutic treatment with ribavirin on development of EAE suggest this nucleoside analogue as a useful candidate for therapy in multiple sclerosis.