Deoxyadenosine diphosphate

P 2 -deoxyadenosine 5 -diphosphate + trans-farnesyl triphosphate S 2 -deoxy-adenosine 5 phosphate -I- trans-farnesyl diphosphate <1> (<1>... 

Nucleotides are nucleosides that have been phosphorylated on the 5 -hydroxyl group. One, two, or three phosphates can be added. Nucleotides are generally named by appending monophosphate, diphosphate, or triphosphate to the end of the name of the corresponding nucleoside, and the names are typically abbreviated. The suffixes -MP, -DP, and -TP correspond to mono-, di-, and triphosphate, respectively. Examples of 2 -deoxyadenosine 5 -diphosphate or ADP (6.13) and uridine 5 -monophosphate or UMP (6.14) are shown in Figure 6.5. 

Cytosine arabinoside p-D-Furanose-/orw 5 -Phosphate, C-221 Cytosine arabinoside p-D-Furanose-/orw 5 -TViphosphate, C-221 2 -Deoxy-5 -adenylic acid, D-28 2 -Deoxyadenosine 5 -Diphosphate, D-28 2 -Deoxyadenosine 5 -TViphosphate, D-28 2 -Deoxy-3 -adenylic acid, D-28 2 -Deoxyadenylyl-(3 ->50-2 -deoxyguanosine, D-31 2 -Deoxycytidine -D-form 5 -Diphosphate, D-43 2 -Deoxycytidine -D-form 5 -Phosphate, D-43 2 -Deoxycytidine -D-form 5 -Triphosphate, D-43 2 -Deoxy-3 -cytidylic acid, D-43 2 -Deoxycytidylyl-(3 50-2 -deoxyadenosine, D-45 2 -Deoxycytidylyl-(3 50-2 -deoxyadenylyl-(3 50-2 -deoxyguanosine, D-46... 

Adenine Deoxyadenosine Deoxyadenyiic acid Deoxyadenosine monophosphate (dAMP) Deoxyadenosine diphosphate (dADP) Deoxyadenosine triphosphate (dATP)... 

When two acid molecules condense by elimination of a molecule of water, the product is called an acid anhydride, as can be seen in Figure 12.60. Acid anhydrides are always very reactive, or high-energy, compounds. When deoxy-adenosine monophosphate forms an anhydride with phosphoric acid, we have deoxyadenosine diphosphate (dADP). Of course, if we add an additional phosphate group, we have deoxyadenosine triphosphate (dATP). 

The overall reaction for the synthesis of, for example, deoxyadenosine diphosphate (dADP)... 

Deoxyadenosine monophosphate Deoxyadenosine diphosphate Deoxyadenosine triphosphate Adenosine monophosphate Adenosine diphosphate Adenosine triphosphate... 

Scheme 14.11. A proposal for the use of ribonucleoside diphosphate reductase (ribonucleotide diphosphate reductase, EC 1.17.4.1) to convert adenosine diphosphate (ADP), uridine diphosphate (UDP), and cytidine diphosphate (CDP) into their respective 2 -deoxy analogues deoxyadenosine diphosphate (dADP),deoxyuridine diphosphate (dUDP),and deoxy-cytidine diphosphate (dCDP), or, in general, ribonucleic acids (RNAs) into the corresponding deoxyribonucleic acids (DNAs) (after Stubbe, J. 7. Biol. Chem., 1990,265, 5330).

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

Deoxyribonucleotides, the building blocks of DNA, are derived from the corresponding ribonucleotides by direct reduction at the 2 -carbon atom of the D-ribose to form the 2 -deoxy derivative. For example, adenosine diphosphate (ADP) is reduced to 2 -deoxyadenosine... 

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

The synthesis of nucleoside diphosphates is best achieved using the Poulter reaction,9 which involves reaction of the tris(tetra-n-butylammonium) salt of pyrophosphate with a nucleoside 5 -tosylate in acetonitrile. A general procedure for the synthesis of nucleoside tosylates of thymidine and 2 -deoxyadenosine is included (Protocol 15), whilst the syntheses of the other tosylates (including ribonucleosides) have been described using related procedures. Simple modification of the protocol, whereby the tetra-n-butylammonium salt of pyrophosphoric acid is replaced by methylene or difluomethylene bis phosphonate, allows the synthesis of hydrolytically stable dNTP analogues.10... 

The reaction of 5 -amino-5 -deoxyadenosine with trimetaphosphate affords the 5 -Af-triphosphate (23). When (23) is employed as substrate with glucose in the hexokinase-catalysed reaction, the 5 -AT-diphosphate (24) is obtained the latter is cleaved by snake venom phosphodiesterase to the 5 -phosphoramidate, and hydrolyses in acid to the amino-nucleoside. It does not appear to be polymerized by polynucleotide phosphorylase. In this context it is noteworthy that uridine 5 -5-thiopyrophosphate (25) is a competitive inhibitor for polynucleotide phosphorylase from E. coli, but not a substrate, and that the 5 -S-thiotriphosphates (26) and (27) show neither substrate nor inhibitory properties for RNA polymerase or DNA polymerase I, respectively. However, (23) can be polymerized using the latter enzyme, showing that the introduction of a 5 -heteroatom does not completely exclude these modified nucleotides as substrates for the polymerizing enzymes. 

The synthesis of the two diastereoisomers of P -l-(2-nitrophenyl)ethyl adenosine S -lri-phosphate (91) has been achieved using resolved (R)- and (5)-l-(2-nilroidienyl)ethanol. The alcohols were converted to (R)- and (5)-l-(2-nitrophenyl)ethyl phosphates by phosphitylation with N,)V-diisopropyl-fi(s-(2-cyanoethyl)phosphoramidite (92) and subsequent oxidation with 3-chlorobenzoic acid. Each of the monophosphates was activated with carbonyidiimidazole and condensed with adenosine diphosphate to give the desired triphosphate. These ATP analogues can be used for the rapid release (by flash photolysis) of ATP in biological systems. The 8-azido-3 -0-anthraniloyl derivatives of 2 -dADP (93) and 2 -dATP (94) have been prepared in seven steps from 8-azido-2 -deoxyadenosine. These compounds are of interest as fluorescent and photoactivatable probes for the nucleotide binding site of kinases and cyclases. In particular, (94) was shown to be a competitive inhibitor of Bordetella pertussis adenylate cyclase and the observed K- (74 pM) was close to tiiat predicted from the K- value of 3 -0-anthraniloyl-2 -dATP. ... 

Pentostatin (Fig. 42.25) is a ring-expanded purine ribonuoleoside that inhibits adenosine deaminase and is used in the treatment of hairy cell leukemia. The elevated levels of deoxyadenosine triphosphate that result from inhibition of this degradative enzyme inhibit the action of ribonucleotide reductase (the enzyme that converts ribose diphosphate to deoxyribose diphosphate), thus halting DNA synthesis within the tumor cell. 

Novel cyclic di- and triphosphate derivatives of 3 -amino-3 -deoxyadenosine-5 -diphosphate (75) and triphosphate (76) have been prepared " by cyclisation of the respective 5 -di- and triphosphate derivatives of 3 -A -Boc-3 -amino-3 -deoxyadenosine using the water-soluble carbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), followed by removal of the Boc protecting group with TFA. The acyclic polyphosphate precursors were prepared according to Yoshikawa and Ludwig after first dissolving the nucleoside in hot triethylphosphate. The reaction proceeds via the intermediacy of the 5 -phosphorodichloridate derivative, partial hydrolysis of which gives the monophosphate, whilst traces of pyrophosphoryl chloride result in... 

The E. coli DNA polymerase I (Pharmacia 3427-0626 E. coli CM 5197), an enzyme already known to be multifunctional (the polymerase and the 3, 5 -exonuclease activity belong to the same polypeptide chain and can be split off only proteolytical-ly) has still other, as yet imsuspected, capabilities. It deaminates 2 -deoxyadenosine to make 2 -deoxyinosine, and reduces ADP to dADP in the presence of dGTP and NADPH. The multifunctional enzyme from E. coli is also active as a nucleoside diphosphate kinase. This last activity has also been observed by A. Kornberg (6). 

---