The Role of the 5′-Hydroxyl Group of Adenosine in Determining Substrate Specificity for Adenosine Deaminase

Bloch, Alexander; Robins, Morris J.; McCarthy, James R.

doi:10.1021/jm00317a034

Cited by 112 publications

(45 citation statements)

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“…Stability toward catabolic enzymes (e.g., adenosine deaminase [ADA], cytidine deaminase, purine nucleoside phosphorylase, hypoxanthine-guanine phosphoribosyltransferase) is also desirable. For example, 2Ј,3Ј-dideoxyadenosine (ddA) is a substrate for mammalian ADA and is easily converted by enzyme-catalyzed hydrolytic deamination to ddI (7,15). Although ddI is fortuitously active against HIV, this instability is not always desirable (62).…”

Section: Introductionmentioning

confidence: 99%

Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry

Nair

Jahnke

1995

Antimicrob Agents Chemother

145

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In summary, many isomeric analogs of ddNs of both D-related and L-related absolute stereochemistries have been synthesized and evaluated in vitro for their antiviral activities. A few of these compounds exhibit potent antiviral activity and, interestingly, belong to both the D and L families. The synthetic methodologies developed will allow accessibility to many more novel modified nucleosides. While some structure-activity relationships are emerging from this work, it is clear that these chiral isomeric nucleosides have opened a new chapter in the field of antiviral nucleosides.

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Section: Introductionmentioning

confidence: 99%

Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry

Nair

Jahnke

1995

Antimicrob Agents Chemother

145

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“…Since the intestinal mucosa has high levels of adenosine deaminase (Ho et al, 1980), a prodrug of 1 that is protected from deamination during absorption may be a more effective oral agent. Substitution of the 2 /-or 5'-hydroxyl of adenosine is known to lead to compounds resistant to the action of adenosine deaminase (Shah et al, 1965;Bloch et al, 1967;Schaeffer et al, 1971;Hampton et al, 1972). In an earlier report we described the synthesis and evaluation of a series of di-and tri-esters of 1, which indicated that the 2' ,3 /-diacetate provided enhanced bioavailability and water solubility, whereas the 2',5 /-and 3',5 /-diacetates showed enhanced bioavailability with diminished aqueous solubility (Jones et al, 1991).…”

Section: -Methoxypurine Arabinoside (9-[i3-d-arabinofuranosyl]mentioning

confidence: 99%

5′Prime;-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

Chamberlain

Moorman

Jones

et al. 1992

Antivir Chem Chemother

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SummaryThe potent and selective activity of 6-methoxypurine arabinoside (9B[I3-D-arabinofuranosyl]-6-methoxy-9H-purine; 1) and its pharmacokinetic limitations have been described previously. In an attempt to circumvent first-pass catabolism following oral administration, a series of 5 ' -esters (2a-t) was prepared by dicyclohexyl-carbodiimide-promoted condensation with formic acid in the case of 2a, or by direct acylation of the parent nucleoside with the corresponding acyl chloride. These compounds were evaluated in rats for efficacy as oral prodrugs of 1 by measuring the amount of 1 excreted in the urine. Both aliphatic and aromatic esters exhibited a range of systemic availabilities. The substituted benzoate esters showed a correlation between the amount of 1 excreted and the electron-donating properties of the substituent. A similar relationship was observed for the relative stabilities of this series of esters to non-enzymatic hydrolysis at neutral pH. No clear relationship between systemic availability and solubility, partition coefficient, or stability was observed for the remaining esters of 1. Although significant enhancements in systemic availability were observed with some of the 5 ' -esters of this series, their limited water solubility precluded their use in intravenous formulations.

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“…Synthetic 9-P-D-xylofuranosyladenine (xyloA) (46, 31) was also shown to exhibit inhibitory activity against neoplastic cells (32). However, both araA and xyloA are rapidly converted to the corresponding 6-0x0 (hypoxanthine) analogs by adenosine deaminase (33)(34)(35), an enzyme with high activity in both mammalian blood and intestinal loci. The incorporation of radioactivity into inosine monophosphate (IMP) and ribonucleic acid (RNA) after treatment with purine-labeled araA has subsequently been shown to result from enzymatic deamination, glycosyl bond cleavage (presumably phosphorolysis), and effective reutilization of the purine moiety as 'salvaged' ribonucleotides (34,35).…”

Section: -8-pivalyl-p-d-xylofuranosyl)pyrrolo[23 -D L -mentioning

confidence: 99%

Nucleic acid related compounds. 25. Syntheses of arabino, xylo, and lyxo-anhydro sugar nucleosides from tubercidin ribo-epoxide

Robins¹,

Fouron²,

Muhs³

1977

Can. J. Chem.

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. Can J. Chem. 55, 1260Chem. 55, (1977. Treatment of the trans iodohydrin acetate, 4-arnino-7-(3-iodo-3-deoxy-2-O-acetyl-5-0-[2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl]-~-~-xylofuranosyl)pyrrolo[2,3-d]pyrimidine (2) with methanolic ammonia gave 2',3'-anhydrotubercidin (3) in 96% yield. N4,N4,05'-Tribenzoylation of 3 gave 4, which is stabilized against intramolecular cyclization. Treatment of 4 with boron trifluoride etherate (3',5'-benzoxonium ion formation) followed by deblocking gave 4-amino-7-B-D-xylofuranosylpyrrolo[2,3-dlpyrimidine (5) in 91% overall yield from tubercidin (1). The 3',5'-0-isopropylidene derivative (6a) of 5 was mesylated to give 6b which was deprotected in acid and the resulting trans hydroxy mesylate was treated with base to give 4-amino-7-(2,3-anhydro-P-D-lyxofuranosyl)pyrrolo[2,3-d]rmdne (7

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The Role of the 5′-Hydroxyl Group of Adenosine in Determining Substrate Specificity for Adenosine Deaminase

Cited by 112 publications

References 0 publications

Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry

Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry

5′Prime;-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

Nucleic acid related compounds. 25. Syntheses of arabino, xylo, and lyxo-anhydro sugar nucleosides from tubercidin ribo-epoxide

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