Cordycepin from adenosine

An improved 4-stage synthesis of 3 -deoxyadenosine (cordycepin) from adenosine has been described, giving a 38SK overall yield. (Scheme 3)... 

Studies on the biogenesis of cordycepin with labeled precursors demonstrated (375,376) that glucose-7- C and glucose-6- C, as well as adenine-8- C, adenosine-and formate- C, were incorporated into cordycepin, whereas ribose-/- C was essentially unutilized. Determining the radioactivity distribution led to the conclusion that cordycepin is generated from adenosine, with retention of the glucoside bond intact. 

Cordycepin (3 -deoxyadenosine) is formed from adenosine by direct reduction. h) Saxitoxin. Certain dinoflagellates form saxitoxin, which also accumulates in marine invertebrates, e.g., in mussels and in the Alaskan clam, which use dinoflagellates as food source. Saxitoxin is a very active neurotoxin for mammals and in the last years caused repeatedly intoxication of human beings. 

Frederiksen, S., H. Malling, and H. Klenow. Isolation of 3 -deoxy-adenosine (cordycepin) from the liquid medium of Cordyceps militaris (L. ex Fr.) Link. Biochim et Biophys. Acta 95, I89 (1965). 

T. brucei is unable to synthesize purines de novo and, as such, is dependent upon salvage mechanisms from the host. A number of transporters and enzymes are used by T. brucei to accomplish this task, and inhibition of these targets offers promise for development of trypanocides [39]. This strategy has been validated by demonstration that cordycepin (34), a substrate for T. brucei adenosine kinase (TbAK), which terminates RNA synthesis and parasite growth, can cure stage 2 HAT infections in mice when coadministered with deoxycoformycin (35), an adenosine deaminase inhibitor [40]. 

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]. 

II = adenosine 12 = cordycepin. Adapted from Reference 33 with permission of Wiley-VCH. 

Cordycepin O -deoxyadenosine 152), isolated from Cordyceps militaris (Cunningham et al., 1951 Bentley et al., 1951), is a deoxynucleoside possessing antifungal, antiviral, and antitumor activity. Although (152) was isolated 50 years ago, there are still an increasing number of publications on the biochemistry of this compound and other nucleoside mimics. It should be noted that an adenosine derivative, N 6-(2-hydroxyethyl) adenosine (153), was isolated, together with (152) and adenosine, from several species of Cordycepsand Isaria (Furuya et al., 1983). 

The adenosine-related metabolites cordycepin (3 -deoxyadenosine, 160), mp 230-23rc, [a] -35°, and 2 -deoxycoformycin (161), mp 220-225°C, [a]g -1-76.4°, have been isolated from the culture broth of Asp. nidulans (237,238). 2 -Deoxycoformycin (161) had been isolated previously from Streptomyces anti-... 

Deoxycoformycin and cordycepin have been isolated from a new strain of Aspergillus nidulans Y176-2 cultured on wheat-bran, the first example of a potent adenosine deaminase inhibitor (2-deoxycoformycin) occurring in a fungus. ... 

The unsaturated nucleoside (53) has been prepared in good yield by electrochemical elimination from either the 2 -bromo-arabino- or the 3-bromo-xylo-nucleoside indicated in Scheme 14 however, the electrolyte can control the product obtained, for whereas 2-bromo-2 -deoxy-3, 5-di-O-propanoyl-uracil gave the 2, 3-unsaturated nucleoside in presence of tetraethylammonium toluene-p-sulphonate in methanol, with sodium acetate a mixture of products was obtained 3-deoxy-3-iodo-adenosine yielded 3-deoxy-adenosine (cordycepin) besides the 2, 3-unsaturated nucleoside.1-Acetyl-glycenose derivatives have been condensed with purine and pyrimidine derivatives in presence of antimony... 

Ribose was assimilated from the culture medium very rapidly, but it failed to contribute a measurable quantity of radioactivity in the isolated cordycepin. Acetate-1and isovalerate-l- C were also used. These studies were based on the assumption that the structure of the sugar was a branch chain pentose. As expected, neither acetate nor the isovalerate were incorporated into 3-deoxyribose. More recently, Suhadolnik et al. (1964b) have shown that adenosine or a phos-phorylated adenosine is the direct precursor for cordycepin. These results were obtained by adding adenosine-U- C to a growing culture of C. militaris. The percent distribution of the carbon-14 in the adenine ribose of the adenosine added to the fermentation medium was 40 60. The distribution of the carbon-14 in the adenine 3-deoxyribose of the cordycepin isolated from two separate experiments... 

The biosynthesis of psicofuranine has been studied by Sugimori and Suhadol-NiK (1965 a and b). Since adenosine was shown to be the direct precursor in the biosynthesis of cordycepin, one biogenetic scheme considered was that of the addition of a Ci unit to carbon atom-1 of ribose in adenosine to form psicofuranine. This Cl unit could arise from formate, formaldehyde, serine or glycine. 

Our recent studies have shown that during the time of cordycepin biosynthesis, DNA synthesis is completely stopped. When adenosine-U- C is added to cordycepin producing cultures of Cordyceps militaris and the RNA and DNA isolated, the RNA is radioactive, while the DNA is not. Both adenine and guanine isolated from the RNA are radioactive. 

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