Synthesis And Characterization Of Ribavirin And Eicar Derivatives And Their Photochemical Property

Ribavirin is the first synthetic nucleoside with a broad spectrum of antiviral activity. It is the only small molecule approved, used in combination with interferon a, to treat HCV patients . Recently, it is used in the context of emergency to treat SARS patients and has found favorable response at the early stage of infection. 5-Ethynyl-l-p-D-ribofuranosylimidazole-4-carboxamide (EICAR) is one of the most potent congeners of ribavirin. Its antiviral potency is approximately 10 to 100 fold times greater than that of ribavirin and now it is being evaluated in Phase III clinical trials.The exact antiviral mechanisms of ribavirin and EICAR are not yet definitely elucidated, although many hypotheses have been proposed. The proposed modes of action included inhibition of host inosine monophosphate dehydrogenase, inhibition of viral RNA polymerase and of viral capping enzymes, lethal mutagenesis of viral RNA genomes and modulation of the host immune response. In order to study the molecular mechanisms responsible for the antiviral activity of ribavirine and EICAR, we proposed a photoaffinity labeling approach. We therefore designed, synthesized and characterized a series of photoprobes of ribavirin and EICAR.Although ribavirin has many superiority over other drugs in clinical to against virus, it also has serious side effect when was treated in large dose. So it is very important to design and synthesize new generations of ribavirine as more efficient and safer antiviral drugs in order to fight against unexpected viral attacks such as SARS or bio-terrorism. For this purpose, we designed and synthesized a series of ribavirin derivatives.The principal results we obtained are folio wings: (1). Photolabeling probes of ribavirin.Photolabeling probes of ribavirine were designed based on the structure ofribavirine and synthesized via different methods. The chemical structure of these probes were confirmed by 'H NMR, IR, MS, UV and the X-ray analysis c.The photodecomposition of the probes were studied in phosphate buffer and in different organic solvents. Our preliminary results suggest that they might be promising photoprobes for the photoaffinity study of the antiviral mechanism of ribavirin.(2). Photolabeling probes of EICAR.Different photolabeling probes of EICAR were designed and synthesized. Among them, the azido probes is the most promising because it is stable in the dark and highly reactive upon irradiation.(3). Azidoimidazole as model compounds for photolabeling A series of diazoimidazole derivates were synthesized as model molecule of photolabeling probes and their photo-property were studied.They undergo rapid photoreaction and give clean photoproducts in different organic solvents. Upon irradiation, they can give insertion products with diethylamine and 2,3-dimethyl-2-butene and form adducts with a wider variety of functional groups such as hydroxy and sulfhydyl groups, though their exact mechanism of photochemistry should be studied in detail.Their photochemistry was further studied in cooperation with Prof. Wirtz in Basel University via methods of low temperature !H NMR, laser flash photolysis, FTIR, UV et al. On the basis of low temperature NMR data, we could show that one product is formed predominantly. Its structure was assigned to cyanoformamidine. The fate of cyanoformamidine is not known. It is a very reactive molecule, might be involved in the further photochemical reaction. The exact mechanism study is underway.(4). New generation of ribavirin and EICAR derivatives.A series of new derivatives of ribavirin and EICAR were designed and synthesized by modify their triazole ring or sugar moiety. We have introduced different groups on the triazole ring in order to improve their ability to form stacking or basepairing. Acyclic triazole nucleosides were also synthesized in view to get better profile of antiviral activity. The synthesized compounds are undergoing biological test in collaboration with Prof. Guo Deying in the College of Life Science, Wuhan University. Further study of the...