Cordycepin synthesis

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]. 

Enzymic discriminations of enantiopic groups of weso-compounds have been widely exploited in asymmetric synthesis. Ohno and co-workers reported a total synthesis of L- and D-ribose, showdomycin and cordycepin based on the optically active half-esters 56 and 57, which were obtained enzymatically (Pig Liver Esterase PLE) from the corresponding mcso-diesters 54 and 55, respectively, derived from the Diels-Alder adduct 53 of furan to dimethyl acetylenedicar-boxylate. The diesters 58 - 60 were also found to be good substrates for PLE leading to the corresponding half-esters 61 - 63 with high enantiomeric purities. ... 

Asymmetric synthesis of stavudine and cordycepin, anti-HIV agents, and several 3 -amino-3 -deoxy-P-nudeosides was achieved utilizing this cycloisomerization of 3-butynols to dihydrofuran derivatives [16]. For example, Mo(CO)6-TMNO-promoted cyclization of the optically active alkynyl alcohol 42, prepared utilizing Sharpless asymmetric epoxidation, afforded dihydrofuran 43 in good yield. Iodine-mediated introduction of a thymine moiety followed by dehydroiodination and hydrolysis of the pivaloate gave stavudine in only six steps starting from allyl alcohol (Scheme 5.13). 

Cordycepin (3 -deoxyadenosine) preferentially inhibits synthesis of ribosomal and tRNA... 

The mechanism of action of abscisic acid (ABA) has been studied to the greatest extent in the barley aleurone system (29), in which ABA counteracts the effect of GA in the induction of hydrolases. This action of ABA has largely been the basis for speculating that ABA may act specifically to inhibit, by some unknown mechanism, DNA-dependent RNA synthesis. Much evidence indicates that ABA acts at the transcriptional level, but it also has been proposed that the inhibition of induction of a-amylase synthesis is caused, at least in part, by an effect on translation because ABA still inhibited the formation of a-amylase at 12 hr when cordycepin (an inhibitor of RNA synthesis) no longer had an effect (30). 

Coralyne, synthesis, 55, 289 Cordycepin analogs, 0-protected, lithiation, 56, 205... 

A potent blocker. How does cordycepin (3 -deoxy adenosine) block the synthesis of RNA ... 

Polymerase inhibition. Cordycepin inhibits poly(A) synthesis at low concentrations and RNA synthesis at higher concentrations. 

Cordycepin terminates RNA synthesis. An RNA chain containing cordycepin lacks a 3 -OH group. 

Fig. 10.24. Gel electrophoresis in discontinuous polyacrylamide gel (3.5 and 10% gels set in tandem, with the concentration discontinuity at the point indicated) of mitochondrial RNA after exposure to the inhibitor cordycepin (cytoplasmic RNA synthesis previously stopped with actinomycin D). From top to bottom, analyses of ( H)-uridine-labeled RNA, 30, 90 and 180 min after addition of cordycepin (Penman...

The role of the poly(A) tail is still not firmly established despite much effort. However, evidence is accumulating that it enhances translation elfi ciency and the stability of mRNA. Blocking the synthesis of the poly(A) tail by exposure to J deoxyadenosine (cordycepin) docs not interfere with iIk synthesis of the primary transcript. Messenger KNA devoid of a poly(A) tail can be transported out ol the nucleus, However, an mRNA molecule devoid of a poly(A) tail is usually a much less effective template tor protein synthesis than is one with a poly(A) tail. Indeed, some mRK As are stored in an unadenylated form and leceive the poly(A) tail only when translation is imminent. The half-life of an m RNA molecule may be determined in part by the rate of degradation of its poly(A ) tail. 

Ohno, M., Ito, Y, Arita, M., Shibata, T., Adachi, K., and Sawai, H., Synthetic studies on biologically active natural products by a chemicoenzymatic approach. Enantioselective synthesis of C- and N-nucleosides, showdomycin, 6-azapseudouridine and cordycepin. Tetrahedron, 40, 145, 1984. 

Cordycepin (3 -deoxyadenosine), an agent that suppresses polyadenylation with a marked reduction of mRNA in cytoplasmic polyribosomes, was investigated with L-tryptophan. Administration of L-tryptophan to fasted rats (1 h before kill) pretreated (2 h) with cordycepin induced a shift in hepatic polyribosomes toward heavier aggregation and an increase in in vitro protein synthesis.120 Also, treatment with L-tryptophan (2.5 h before killing) and cordycepin 0.5 h later enhanced hepatic polyribosomal aggregation and protein synthesis.188 Thus, L-tryptophan acted in a preventative and curative manner. 

In some experiments concerned with the mechanism by which tryptophan acted to improve hepatic protein synthesis after toxic injury, the ability of tryptophan to stimulate hepatic mRNA synthesis, nucleocytoplasmic translocation of RNA in vitro, and nuclear envelope nucleoside triphosphatase activity after hepatotoxic injury was measured.188 Nucleoside triphosphatase (Mg2+-dependent adenosine triphosphatase, EC 3.6.1.3.1) was assayed since it is present in mammalian liver nuclear envelopes,224 and there is evidence that this enzyme is involved in nucleocytoplasmic translocation of RNA.221 All of these parameters were elevated significantly by tryptophan after agents such as actinomycin D, cordycepin, ethionine, puromycin, and hypertonic NaCl demonstrated a curative effect by tryptophan, but not after tryptophan following CC14, NaF, and sparsomycin demonstrated no improvement with tryptophan. These findings emphasized the importance of the role that tryptophan plays in stimulating the availability of cytoplasmic... 

Previous synthetic studies that have employed ozonolysis as a means for cleaving oxabicydic substrates include Meinwald s studies toward pederin [138], Just s synthesis of showdowmycin [139], Masamune s synthesis of avenaciolide [140], and Ohno s asymmetric syntheses of (+)-showdowmycin, (-)-cordycepin C, and (-)-6-azapseudouridine [141 a]. 

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