Formycin synthesis

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). 

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. 

The first step of this sequence, which is not unique to de novo purine nucleotide biosynthesis, is the synthesis of 5-phosphoribosylpyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate. Phosphoribosyl-pyrophosphate synthetase, the enzyme that catalyses this reaction [278], is under feedback control by adenosine triphosphate [279]. Cordycepin interferes with thede novo pathway [229, 280, 281), and cordycepin triphosphate inhibits the synthesis of PRPP in extracts from Ehrlich ascites tumour cells [282]. Formycin [283], probably as the triphosphate, 9-0-D-xylofuranosyladenine [157] triphosphate, and decoyinine (LXXlll) [284-286] (p. 89) also inhibit the synthesis of PRPP in tumour cells, and this is held to be the blockade most important to their cytotoxic action. It has been suggested but not established that tubercidin (triphosphate) may also be an inhibitor of this reaction [193]. 

Steady-state and time-resolved emission spectroscopy was used to study the interaction of E. colt PNP with its specific inhibitors formycin B, FA, and A -l-methylformycin A. Complexation was found to induce tautomeric shifts <2000BBA1467>. Carbocyclic analogues of formycin A and B have been recently synthesized <2004T8233>. The synthesis utilized 417 as starting material which was converted into 418 via a multistage synthesis. The latter could be converted into the formycin analogue (Scheme 36) <2004TL8233>. 

Isolation and characterization of the nucleoside antibiotic formaycin as 3-j8-ribofuranosylpyrazolo[4,3-[Pg.346]

Formycin A was initially isolated from rice mold <65JAN259> and identified <66JHC110, 66TL597) as 3-ribofuranosylpyrazolo[4,3-G ]pyrimidine-7-amine (54a). The reported synthesis utilizes the pyra-zole derivative (522) as starting material which is converted in situ on treatment with zinc dust in methanol in the presence of ammonium chloride into the amine (523) which is then reacted with formamidine to yield formycin A after deprotection (Scheme 53) <78CCC1431>. 

A synthesis of formycin A employs the 1,4-dinitropyrazole (524) which is converted into the nitrile (525) on treatment with cyanide ion (Equation (72)). The latter is then reduced and treated with formamide or formamidine to give formycin A (54a) <80CJC2624,8lJCS(Pl)2374, 91JCS(P1)1077>. 

Formycin B (528) is prepared from the pyrazole (529) by treatment similar to that reported for the synthesis of formycin A (54a) from (523) (72CCC2786). 

This reaction has been used as the key step in an original synthesis of formycin (80CJC2624). By a similar mechanism, via a 3H-indazole, the 2,5-dlnitro derivative reacts with secondary amines to afford 3-amino-5-nltroindazoles (80MI40404, 8UOC2706, 82PNA4487). 

Formamidine acetate is a useful reagent because it can provide a C—N unit to synthesize a pyrimidine ring, e.g. as in Scheme 69 (74JOC2023). Another important example is seen in a synthesis of the antibiotic formycin (223 Scheme 70) (80CJC2624). 

The first synthesis of formycin (386) was reported in 1971 using the nucleoside-nucleoside transformation approach [71JCS(C)2443]. Formycin B (387) was O-acetylated and transformed to the 6-chloropyrazolo[4,3-r/]pyrimidin-3-yl derivative 396. Amination of 396 with liquid ammonia gave formycin (386) (Scheme 112). 

Synthesis of formycin by the stepwise assembly of the pyrazolopyrimidine system onto the sugar moiety was accomplished by Kalvoda in Czechoslovakia (78CCC1431). The starting material utilized in this synthesis was the... 

A carefully designed synthesis of formycin was published by Buchanan and his group in Scotland and involved a dne-substitution of the 1,4-dinitro-... 

The most commonly used strategy for the synthesis of this class of C-nucleosides was the annulation of the 1,3,5-triazine ring onto suitably substituted pyrazol-4-yl C-nucleosides. Thus, the C-nucleosides 836, related to adenosine and formycin, was prepared by reacting the 3-aminopyrazol-... 

Purine salvage enzymes - The drugs allopurinol (see here) and formycin B inhibit the action of cellular purine salvage enzymes. Thus, these drugs can be used to treat individuals infected by the parasitic protozans, Plasmodium, and Leishmania because these parasites lack the capacity for de novo purine synthesis (i.e., they depend entirely upon cellular purine salvage enzymes and bases provided by the host)... 

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