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New conjugates of antiviral nucleoside Ribavirin (=1-( β- D-ribofuranosyl)-1 H-1,2,4-triazole-3-carboxamide; 1) with 1,2- and 1,3-diacyl glycerophosphates have been synthesized by the phosphoramidite method. A combination of 2′,3′-phenylboronate protecting group for the sugar moiety of the ribonucleoside 1 and 2-cyanoethyl protection for the phosphate fragment ensured the preparation of the desired compounds with reasonable yields via a small number of synthetic steps. [ABSTRACT FROM AUTHOR]

Six non-conventional adenosine-2′- and 3′-triphosphate analogues of ATP were tested as potential phosphate donors for all four human, and D. melanogaster, deoxyribonucleoside kinases. With dCK (only dAdo as acceptor), TK1, TK2 and dNK only 3′-deoxyadenosine-2′-triphosphate was an effective donor (5–60% that for ATP). With dCK (dCyd as acceptor) and dGK (dGuo as acceptor), sharing 45% sequence identity, donor activities ranged from 13 to 119% that for ATP. Products were 5′-phosphates. In some instances, kinetics are dependent on the nature of the acceptor, and donor and acceptors properties are mutually interdependent. Results are highly relevant to studies on the modes of interaction with the enzymes, and to interpretations of reported crystal structures of dCK and dNK with bound ligands. [ABSTRACT FROM AUTHOR]

In extension of an earlier report, six non-conventional analogues of ATP, three adenosine-2′-triphosphates (3′-deoxy, 3′-deoxy-3′-fluoro- and 3′-deoxy-3′-fluoroxylo-), and three adenosine-3′-triphosphates (2′-deoxy-, 2′-deoxy-2′-fluoro- and 2′-deoxy-2′-fluoroara-), were compared with ATP as potential phosphate donors for human deoxycytidine kinase (dCK), cytosolic thymidine kinase (TK1), mitochondrial TK2, deoxyguanosine kinase (dGK), and the deoxyribonucleoside kinase (dNK) from Drosophila melanogaster. With one group of enzymes, comprising TK1, TK2, dNK and dCK (with dAdo as acceptor), only 3′-deoxyadenosine-2′-triphosphate was an effective donor (5–60% that for ATP), and the other five analogues much less so, or inactive. With a second set, including dCK (dCyd, but not dAdo, as acceptor) and dGK (dGuo as acceptor), known to share high sequence similarity (approx. 45% sequence identity), all six analogues were good to excellent donors (13–119% that for ATP). With dCK and ATP1, products were shown to be 5′-phosphates. With dCK, donor properties of the analogues were dependent on the nature of the acceptor, as with natural 5′-triphosphate donors. With dCK (dCyd as acceptor), Km and Vmax for the two 2′(3′)-deoxyadenosine-3′(2′)-triphosphates are similar to those for ATP. With dGK, Km values are higher than for ATP, while Vmax values are comparable. Kinetic studies further demonstrated Michaelis-Menten (non-cooperative) or cooperative kinetics, dependent on the enzyme employed and the nature of the donor. The physiological significance, if any, of the foregoing remains to be elucidated. The overall results are, on the other hand, highly relevant to studies on the modes of interaction of nucleoside kinases with donors and acceptors; and, in particular, to interpretations of the recently reported crystal... [ABSTRACT FROM AUTHOR]

A one- and two-dimensional NMR study has been performed on seven A(2'-5')A(2'-5')A fragments containing 9-(3'-fluoro-3'-deoxy-β-D-xylofuranosyl)-adenine (AP) or 3'-fluoro-3'-deoxyadenosine (AP) residues at different positions, and on the corresponding monomers. A(2'-5')A(2'-5')A' served as a reference compound. The fluoro substituent governs the conformation of the sugar ring: an AP residue displays mainly N-type sugar and the ring is considerably flattened (θN ≈ 30°) comparedd to AP. residues (θ ≈ 40°), which exhibit almost pure S-type conformation. Moreover. in AP moieties the rotamer distribution around torsion angle γ-(05'-C5'-C4'-C3') and the base orientation are influenced to a large extent by the presence of the fluorine substituent. The sugar rings of nonflourinated residues in the trimers appear rather flexible. A possible correlation between the conformational characteristics of the fluorinated fragments and their biological activity has been found: the fragments that meet the prerequisites for binding to RNase L indeed show enhanced binding to this endonuclease. Furthermore, substitution of the 3'-OH group of the second residue by hydrogen or of the 3'-OH group of the 2'-terminal residue by fluorine or hydrogen results in increased resistance towards 2'-5'-phosphodiesterase. [ABSTRACT FROM AUTHOR]

The review is devoted to the development and study of the drug Leukovir ® (cladribine+ ribavirin) and its use in the treatment of relapsing-remitting and secondary progressive forms of multiple sclerosis, a chronic neurodegenerative disease aiming the risk reduction of relapse and progression of a disability. In clinical trials Leukovir ® has proved to be efficient by up to 56 weeks for the treatment of relapsing-remitting and secondary progressive forms of multiple sclerosis. The drug is registered in the Republic of Belarus. The efficacy, safety and tolerability profile of the drug Leukovir ® suggests that it is well suited for disease-modifying therapy of multiple sclerosis. Patients require four 35-day courses of treatment, each consisting of seven days of treatment followed by a break of 28 days. The use of Leukovir ® has contributed to the suppression of inflammatory process activity according to MRI data and stabilization of the clinical condition. It has reduced the number of relapses in patients with relapsing-remitting and secondary-progressive forms of multiple sclerosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Convergent synthesis of 9-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)adenine is described starting from methyl 5-O-benzyl-2-deoxy-2-fluoro-alpha-D-arabinofuranoside.