C-nucleosides: aspects of chemistry and mode of action

Among the relatively few naturally occurring nucleosides, which contain ribose bound to a carbon atom of the heterocyclic aglycone. some—the formycins. oxazinomycin, pyrazomycin, and showdomycin—appear to act as antagonists to essential metabolites, whereas otbers—pseudo-uridine, also formycin A— appear to resemble their respective counterparts—uridine, adenosine—to such degree as to be capable of functioning as metabolic substitutes. Recent studies have focused on the effects of C-nucleosides on ribonucleotide reductase and purine ribonucleoside phosphorylase, on the mode of action of C-nucleosides and on their biosynthesis. The properties of polymers and co-polymers of formycin have been interpreted in terms of the relative contributions of the 'syn-' and 'anti-' conformations of this C-nucleoside (Ward, Reich). The observation of specific reversal of anti-viral activity of pyrazomycin by uridine alone points to pyrimidine biosynthetic pathways as the possible vulnerable site for growth inhibition. Support for this notion derives from experiments with orotidylic decarboxylase of rat liver, 50 per cent inhibition of activity being observed at levels of 5 x 108M pyrazomycin-5'-phosphate. The antimicrobial activity of oxazinomycin (Haneishi et a!.. Sankyo Ltd., Tokyo) was efficiently reversed only by deoxycytidine. perhaps suggesting nucleotide reductase as site of action. The synthesis of showdomycin and of oxoformycin has recently been accomplished (F. Sorm et al., Prague), while 'pseudo-azauridine' has been obtained by conversion of pseudo-uridine (Sorm). The agricultural potential of formycin B against rice plant disease has been noted but no medical usefulness has thus far been demonstrated for members of the C-nucleoside class. The preparation of additional C-nucleosides by synthesis or by modification of naturally available materials, together with a detailed understanding of structure-activity relationships, hopefully will assist in the realization of the therapeutic potential of this versatile class of