Formycin

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

Aminopyrazolo[4,3-d]pyrimidine moiety (47) is present in several nucleosides of both biological and synthetic origins. Among them, formycin (47, R = 3/3-D-ribofuranozyl) is of particular interest as a C-nucleoside analog of adenosine. 

Among some 70 new antitumor compounds discovered by H. Umezawa and coworkers, formycin (1966) constituted another important discovery. Produced in conjunction with coformycin, the latter inhibits the activity of adenosine deaminase (1967) and enhances the antitumor activity of formycin. 

All of Hamao U mezawa s work was closely connected with carbohydrates. The principal compounds that he developed, namely, kanamycin, dibekacin (with the elucidation of the resistance mechanism), kasugamycin, formycin, bleomycin, and anthracyclines, are all glycosides. The l.m.w. enzyme-inhibitors, exemplified by bestatin, are mostly oligopeptides, and are the only exceptions. 

FG King, RL Dedrick. Physiological model for the pharmacokinetics of 2 -deoxyco-formycin in normal and leukemic mice. J Pharmacokin Biopharm 9 519-534, 1981. 

The molecule 7-aminopyrazolopyrimidine is related to the DNA base adenine. It is the base attached to ribose in formycin A, which is believed to have potential therapeutic value. It is also shown in Figure 5. There is a paradox in this system. This molecule is deactivated by the enzyme adenosine deaminase (ADA). In solution the N7H tautomer predominates. This structure however inhibits ADA, and this tautomer of formycin A would not be deactivated by the enzyme. 

The nitrile group in 82 has been transformed into other versatile functional groups, and the derivatives so obtained have been used in the synthesis of various naturally occurring C-nucleosides and their analogs. Reduction of 82 with lithium aluminum hydride gave the amine 90 which was, in turn, transformed84 into the ureido and N-ni-troso derivatives (91-93) by treatment with nitrourea, followed by benzylation, and nitrosation.85 The diazo derivative 94, obtained by treatment of 93 with alcoholic potassium hydroxide, was a key intermediate in the synthesis of formycin B and oxoformycin B (see Section III,2,a,b). 

Grouped in this Section are the C-D-pentofuranosyl-imidazoles, -pyrazolopyrimidines, and -adenines. The last two analogs are positional isomers of formycin in which the heterocyclic moiety is attached to the sugar at an unnatural position. A rationale103 for the synthesis of this type of analog is of interest it was based on the possibility of a close structural similarity between a natural adenine nucleoside and synthetic analog with respect to available hydrogenbonding sites. 

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