Synthesis and study of certain derivatives of the C-nucleosides formycin and formycin B
Creators: name: Lewis, Arthur Frank
Publisher: name: University of Utah
Year: 2012
Subjects: Organic Compounds
Synthesis

description: Methylation of formycin under non-basic reaction conditions has afforded 4-methylformycin and 6-methylformycin.  The structures assigned to these two mono-N0methyl isomers of formycin were based on ultraviolet and nuclear magnetic resonance spectral studies. N7-methylformycin has been resynthesized by an alternate and more facile route.  Some of the physio-chemical properties of the five N-methylisomers of formycin have been tabulated and compared.  Certain spectral characteristics were found to distinguish 6- methylformycin for other ring-methylated isomers.  Additionally, 6-methylformycin was found to unstable in aqueous solution, yielding three products, formycin B, N7-methylformycin and 6-methylformycin B.  The first two products of this reaction were identified by direct comparisons to authentic materials.  A confirmation the 6-methylformycin B was the third product involved the unambiguous synthesis of 3,6-dimethylpyrazolo[4,3-d]primidin-7-one and follower by a comparative study of its ultraviolet spectra.  However, the structure of the third product was not confirmed by this method and led to the synthesis of 6-methylformycin.  A comparison of the 6-methylformycin B prepared in this manner with the third product obtained from the reaction of boiling water with 6-methylformycin confirmed that the third product was indeed 6-methylformycin B.  The two remaining, unknown, mono-N-methyl formycin B derivatives have also been synthesized by the reaction of nitrosyl chloride with 4-methylformycin and 1-methylformycin.  Studies have shown that formycin derivatives methylated in the pyrimidine ring do no inhibit the growth of L-1210 cell cultures.   Associated studies have also found that 4-methylformycin and 6-methylformycin were not substrates for either adenosine deaminase or adenosine kinase from human erythrocytes.  Certain structure activity relationships for the methylated formycins have been drawn from these results.  Formycin-5'-triphosphate has been synthesized using standard methods of nucleotide preparation.  A collaborative study has investigated the interaction of formycin-5'-triphosphate with the nucleotide reductase from Lactobacillus leichmannii.  The preliminary results of this study indicate that the enzymatic reduction of formycin is a viable alternate to established routes for the synthesis of 2'-deosyformycin.  The versatile synthetic intermediate 4-amino-3-(?-D-ribofuranosyl)pyrazole-5-carboxamide has been resynthesized by an alternate, more efficacious rout which involves the acidic ring fission of the pryrimidine moiety of formycin-N6-oxide.  This amino analog of the C-nucleoside antibiotic pyrazofurin was not inhibitory to the growth of L-1210 cell cultures.  Annulation of amino-3-(?-D-ribofuranosyl)pyrazole-5-carboxamide has afforded 5-amino-3(?-D-ribofuranosyl)pyrazole[4,3-d]-pryimidin-7-one (5-aminoformycin B), a C-nucleoside analog of guanosine.  The synthesis of 5-aminoformycin B was preceded by model studies which produced the guanine analog, 5-aminopyrazolo[4,3,-e]-pryimidin-7-one.