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PubMed1995

2',3'-Dideoxyadenosine killing of TdT-positive cells is due to a trace contaminant.

We have previously reported that the chain-terminating nucleoside analogue 2',3'-dideoxyadenosine (ddA) is specifically cytotoxic for TdT-positive cells in the co-presence of the adenosine deaminase (ADA) inhibitor coformycin (CF). Further studies with ddA/CF revealed that cytotoxicity occurs only if ddA is supplied from the Calbiochem or Fluka companies. ddA supplied from other commercial sources (Pharmacia, Sigma) or the NCI Pharmaceutical Resources Branch is non-cytotoxic. To explore the basis for this difference, ddA from various sources was subjected to reverse-phase high-pressure liquid chromatography (HPLC) analysis. The Calbiochem and Fluka ddA had a unique HPLC peak, with a retention time of 12.8 min, representing a contaminant of less than 0.1% of the bulk material applied to the C-18 HPLC column. Study of all HPLC peaks resolved from the bulk material showed cytotoxic activity in only the 12.8 min peak. To identify the nature of the unknown compound, we compared HPLC characteristics of the synthetic intermediates and byproducts of ddA synthesis to the peak eluting at 12.8 min. Of these, only 3'-deoxyadenosine (cordycepin) had similar HPLC characteristics. In addition, in the co-presence of CF, cordycepin was specifically cytotoxic (IC50 < 0.5 microM) for all TdT-positive cell lines tested. Cytotoxicity was seen in TdT-negative cells only at concentrations 10-100-fold higher. We conclude that our previous report on ddA/CF as a TdT-specific cytotoxic combination was due to contamination of the ddA supplied by Calbiochem by cordycepin. ddA itself is non-cytotoxic for TdT-positive cells. Cordycepin in the co-presence of an ADA inhibitor may be effective in the treatment of TdT-positive hematological malignancies.

Cell Survival↗
PubMed1999

cycloSal-Pronucleotides of 2',3'-dideoxyadenosine and 2', 3'-dideoxy-2',3'-didehydroadenosine: synthesis and antiviral evaluation of a highly efficient nucleotide delivery system.

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.

3T3 Cells↗
PubMed1996

2',5'-Dideoxyadenosine 3'-polyphosphates are potent inhibitors of adenylyl cyclases.

2',5'-Dideoxyadenosine 3'-di- and triphosphates were tested as inhibitors of brain adenylyl cyclases. With an IC50 approximately 40 nM, 2',5'-dideoxy-3'-ATP is the most potent nonprotein synthetic regulator of adenylyl cyclases thus far described. Neither 2',5'-dideoxy-3'-ADP nor 2',5'-dideoxy-3'-ATP inhibited activity by competition with substrate, and the linear noncompetitive inhibition observed was consistent with interaction via a distinct domain. The availability of this ligand will permit the development of a variety of probes that will be extremely useful in investigating adenylyl cyclase structure and the role(s) that this class of compound may play in physiologically regulating cell function.

Adenylyl Cyclase Inhibitors↗
PubMed1999

Enzymatic synthesis of unlabeled and beta-(32)P-labeled beta-L-2', 3'-dideoxyadenosine-5'-triphosphate as a potent inhibitor of adenylyl cyclases and its use as reversible binding ligand.

beta-L-2',3'-Dideoxyadenosine-5'-triphosphate (beta-L-2', 3'-dd-5'-ATP) was prepared enzymatically from the corresponding monophosphate by the use of adenylate kinase, creatine phosphate, and creatine kinase in a single step. The beta-(32)P-labeled analog was prepared similarly, but in a two step reaction. beta-L-2', 3'-dd-5'-ATP inhibited adenylyl cyclase from rat brain competitively with respect to substrate (5'-ATP.Mn(2+)) and exhibited an IC(50) approximately 24 nM. The labeled ligand was used in the development of a reversible binding assay for adenylyl cyclases. Binding of beta-L-2',3'-dd-[beta-(32)P]5'-ATP was saturable with increasing concentrations of ligand and increased in proportion to membrane protein, and was enhanced by Mn(2+) to a greater extent than by Mg(2+). Binding was displaced with adenine nucleotides known to be either competitive or noncompetitive inhibitors but not by agents known not to act on the cyclase, or by 3-isobutyl-1-methylxanthine, creatine phosphate, or creatine kinase. Binding was rapid, with a half-time for the on-rate <1.8 min and for the off-rate <0.8 min. The potency and mechanism of the inhibition of this ligand and the pattern of agents that displace binding suggest an interaction with adenylyl cyclase per se and to a configuration of the enzyme consistent with an interaction at the catalytic active site. The data suggest that this is a pretransition state inhibitor and contrasts with the equipotent 2',5'-dd-3'ATP, a post-transition state noncompetitive inhibitor.

Adenosine Triphosphate↗
PubMed1992

Interpretation of the roles of adenylosuccinate lyase and of AMP deaminase in the anti-HIV activity of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.

Some 2',3'-dideoxynucleotides, of importance in the enzymology of the anti-HIV compounds, ddA and ddI, have been synthesized and purified by ion-exchange chromatography. 2',3'-Dideoxyadenylosuccinate, an intermediate in the pathway of ddI to ddATP, is converted to ddAMP by AMPS lyase at 1.85% of the efficiency of the natural substrate, adenylosuccinate. Interestingly, ddAMP and other 2',3'-dideoxygenated nucleotides are not substrates for AMP deaminase, another relevant enzyme in the conversion of ddA to ddATP via ddI.

AMP Deaminase↗
PubMed2005

Phosphoramidate derivatives of 2',5'-dideoxyadenosine as potential inhibitors of the EDHF phenomenon.

P-site inhibitors of adenyl cyclase, such as the dideoxynucleosides 2',3'-ddA and 2',5-ddA, have been shown to attenuate EDHF phenomenon in rabbit arteries and veins. In order to present the dideoxynucleosides as pre-activated nucleotides and bypass the kinase, as well as to prevent their metabolism to dideoxyinosine by adenosine deaminase, the aryloxyphosphoramidate approach has been successfully applied, initially on the 2',3'-ddA. In the present work a new series of 2',5'-ddA phosphoramidates has been synthesized, representing the first example of phosphoramidate protide not at the 5'-position.

Adenylyl Cyclase Inhibitors↗
PubMed2000

Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine

[formula: see text] L-(1'S,3'S)-9-[3-Fluoro-3-(hydroxymethyl)cyclopentan-1-yl]adenine 15 has been synthesized from ester 2, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 1 in six steps. The key ring closure has been accomplished through an intramolecular nucleophilic substitution reaction.

Journal Article↗
PubMed1995

Cyclic AMP is an essential factor in immune responses.

In the present studies, cAMP, a secondary messenger historically viewed as a negative mediator of immune responses, was demonstrated to possess immunoenhancing activity at low concentrations. In parallel experiments the adenylate cyclase inhibitor, 2',3'-dideoxyadenosine, produced a marked inhibition of humoral and proliferative immune responses suggesting that cAMP at physiologically relevant concentrations acts as a critical second messenger in immune responses. Direct addition of dibutyryl cAMP (10-100 microM), a membrane permeable cAMP analog, to mouse spleen cell cultures produced a marked and dose-related increase (25-100%) in humoral immune responses as measured by the primary IgM antibody forming cell response to the antigen, sheep erythrocytes. Over a similar concentration range, dibutyryl cAMP (5-50 microM) also dose-dependently enhanced (25-50%) phorbol 12-myristate 13-acetate/ionomycin-stimulated lymphoproliferation. Incubation of spleen cells with 2',3'-dideoxyadenosine (40-80 microM), an adenylate cyclase inhibitor, for 30 min depressed significantly the basal level of intracellular cAMP. 2',3'-dideoxyadenosine treatment also significantly decreased both the antibody forming cell response and the proliferative response in a dose-dependent manner. Interestingly, the antibody forming cell response exhibited significantly greater sensitivity to inhibition by 2',3'-dideoxyadenosine than the lymphoproliferative responses. The critical role for cAMP as a positive immunoregulatory signal is further supported by the fact that the immunosuppression by 2',3'-dideoxyadenosine could be reversed completely in the antibody forming cell response to sheep erythrocytes through the addition of dibutyryl cAMP into the culture medium. Partial but not complete reversal of the inhibitory effects of 2',3'-dideoxyadenosine on lymphoproliferation was also demonstrated by dibutyryl cAMP. Taken together, these results suggest that cAMP acts as a positive regulatory signal for immune responses as indicated by the fact that depletion of intracellular cAMP induces a marked inhibition of humoral and proliferative responses.

Animals↗