Tetraethyldicyanoborane pyrophosphate (2) and 3'-(diethylphosphite-cyanoborano)-5'-dimethoxytrityl.N(4)-benzoyl-deoxycytidine (3) have been synthesized in 70% and 76% yields, respectively. The compatibility of the substituted boranophosphates with common protecting groups is hereby demonstrated.Boron containing biologically active compounds, such as nucleosides and nucleotides (1-6) and amino acids (7-9) are important due to their potential therapeutic activity, research and diagnostic applications. Many boron containing compounds have shown promising activity as anticancer, (10.) (11.) (12) antiinflammatory,(13) and antiosteoporotic (13)agents. Oligonucleotdes in which a non-bridging oxygen atom is replaced by a borane(BH(3)) group are a very important class of modified nucleic acids. (1.) (3.) (14-16) The BH(3) group is isoelectronic with oxygen in natural oligonucleotides and isoelectronic and isostructural with the oligonucleotide methyl phosphonates, which are nuclease resistant. On the other hand, the alpha-borano triphosphates are good substrates for DNA polymerases and incorporation of boranophosphates into DNA causes an increase in the resistance to exo- and endonucleases (2.) (17a) as compared to non-modified DNA. There are also notable applications of the alpha-borano triphosphates in PCR sequencing (17a) and nucleic acid detection (17b).
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Tetraethyldicyanoborane pyrophosphate (2) and 3'-(diethylphosphite-cyanoborano)-5'-dimethoxytrityl.N(4)-benzoyl-deoxycytidine (3) have been synthesized in 70% and 76% yields, respectively. The compatibility of the substituted boranophosphates with common protecting groups is hereby demonstrated.
View Article and Find Full Text PDFAcyclic phosphonate nucleotides and human adenylate kinases: impact of a borano group on alpha-P position.
Nucleosides Nucleotides Nucleic Acids
April 2008
Laboratoire d'Enzymologie, Université Paris, Paris, France.
Adenylate kinases are involved in the activation of antiviral drugs such as the acyclic phosphonates analogs PMEA and (R)PMPA. We examine the in vitro phosphorylation of PMEA and PMPA bearing a borano- or a H- group on the phosphorus atom. The alpha-borano or alpha-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 1 and 2.
View Article and Find Full Text PDFSynthesis of AZT 5'-triphosphate mimics and their inhibitory effects on HIV-1 reverse transcriptase.
J Med Chem
December 2004
Research Laboratories, Biota, Inc., 2232 Rutherford Road, Carlsbad, CA 92008, USA.
In search of active nucleoside 5'-triphosphate mimics, we have synthesized a series of AZT triphosphate mimics (AZT P3Ms) and evaluated their inhibitory effects on HIV-1 reverse transcriptase as well as their stability in fetal calf serum and in CEM cell extracts. Reaction of AZT with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, followed by treatment of the phosphite intermediate 2 with pyrophosphate analogues, yielded the cyclic triphosphate intermediates 4b-4f, which were subjected to boronation and subsequent hydrolysis to give AZT 5'-alpha-borano-beta,gamma-bridge-modified triphosphates 6b-6f in moderate to good yields. Reaction of the cyclic intermediate 4d with iodine, followed by treatment with a series of nucleophiles, afforded the AZT 5'-beta,gamma-difluoromethylene-gamma-substituted triphosphates (7b-7i).
View Article and Find Full Text PDFImproving nucleoside diphosphate kinase for antiviral nucleotide analogs activation.
J Biol Chem
October 2002
Régulation Enzymatique des Activités Cellulaires, CNRS FRE 2364, Institut Pasteur, 25, rue du Dr. Roux 75724, Paris cedex 15, France.
Antiviral nucleoside analog therapies rely on their incorporation by viral DNA polymerases/reverse transcriptase leading to chain termination. The analogs (3'-deoxy-3'-azidothymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and other dideoxynucleosides) are sequentially converted into triphosphate by cellular kinases of the nucleoside salvage pathway and are often poor substrates of these enzymes. Nucleoside diphosphate (NDP) kinase phosphorylates the diphosphate derivatives of the analogs with an efficiency some 10(4) lower than for its natural substrates.
View Article and Find Full Text PDFStructural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase.
EMBO J
July 2000
Laboratoire d'Enzymologie et Biochimie Structurales, UPR-9063 CNRS, 91198 Gif-sur-Yvette, France.
AIDS chemotherapy is limited by inadequate intracellular concentrations of the active triphosphate form of nucleoside analogues, leading to incomplete inhibition of viral replication and the appearance of drug-resistant virus. Drug activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase were studied comparatively. We synthesized analogues with a borano (BH(3)(-)) group on the alpha-phosphate, and found that they are substrates for both enzymes.
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