92586-35-1

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• 30516-87-1 3'-azido-2',3'-deoxythymidine 

Relevant academic research and scientific papers

The production and evaluation of antibodies for enzyme immunoassay of AZTTP

We describe the development of the first enzyme immunoassay for quantifying AZTTP that does not use of radioactive labeling. Anti-AZTTP antibodies were raised in rabbits by immunizing with an AZTTP-kelhoyle limpet hemocyanin (KLH) conjugate. Competitive immunoassays indicated a nanomolar sensitivity to AZTTP. One of the antisera produced was specific for AZTTP.

Selective diphosphorylation, dithiodiphosphorylation, triphosphorylation, and trithiotriphosphorylation of unprotected carbohydrates and nucleosides

(Chemical Equation Presented) Aminomethyl polystyrene resin-bound linkers of p-acetoxybenzyl alcohol were subjected to reactions with diphosphitylating and triphosphitylating reagents to yield the corresponding polymer-bound diphosphitylating and triphosphitylating reagents, respectively. A number of unprotected carbohydrates and nucleosides were reacted with the polymer-bound reagents. Oxidation with tert-butyl hydroperoxide or sulfurization with Beaucage's reagent, followed by removal of cyanoethoxy group with DBU and the acidic cleavage, respectively, afforded only one type of monosubstituted nucleoside and carbohydrate diphosphates, dithiodiphosphates, triphosphates, and trithiotriphosphates with high regioselectivity.

Potential lipophilic nucleotide prodrugs: Synthesis, hydrolysis, and antiretroviral activity of AZT and d4T acyl nucleotides

Three general methods for the synthesis of acyl nucleotides (mono-, di-, and triphosphates) have been developed and applied to different HIV inhibitors. These new types of compounds, where a fatty acid moiety is linked to the nucleotide phosphate chain by an acyl phosphate bond, were designed as lipophilic prodrugs of HIV inhibitors metabolites. Acyl nucleoside monophosphates 1a,b were prepared by acylation of the corresponding nucleoside monophosphates. Acyl nucleoside diphosphates 2a-c and 3a,b were synthesized directly from the free nucleosides using DCC activation of acyl pyrophosphates. Acyl nucleoside triphosphates 4a-c and 5a were obtained using phosphoromorpholidate chemistry and acyl pyrophosphates as nucleophiles. Hydrolysis of acyl nucleotides liberated the corresponding nucleotides by selective cleavage of the acyl phosphate bond, with half lives ranging from 51 to 185 h at 37°C in triethylammonium acetate buffer pH 7.0. Their antiretroviral activity, measured by the inhibition of cytopathogenicity and reverse transcriptase activity in the cultures supernatants, did not reveal any differences between an acyl nucleotide and its corresponding nucleotide. These results are explained in term of rapid aminolysis of the acyl phosphate bond in culture media.

New Thymidine Triphosphate Analogue Inhibitors of Human Immunodeficiency Virus-1 Reverse Transcriptase

Several novel imidotriphosphate analogues of thymidine have been synthesized and have been shown to be effective inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT).When the α,β-bridging oxygens of thymidine triphosphate (TTP) and 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) were replaced by a nitrogen, the resulting analogues were no longer substrates but instead became competitive inhibitors of HIV-1 RT.The most potent of the α,β-imidotriphosphate derivatives tested was thymidine 5'-triphosphate (TMPNPP, 1a).This analogue has a Ki value of 2.4 μM inhibiting HIV-1 RT 400-fold more potently than in inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-triphosphate (AZTMPNPP, 1b) gave a Ki value about 10-fold greater than that for TMPNPP, indicating that a 3'-azido substituent decreases the affinity of AZTTP to HIV-1 RT relative to the normal 3'-OH substituent.Dideoxythymidine 5'-triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a Ki value of 15 μM.In contrast, substitution at the β,γ-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent α,β-phosphate linkage, and 3'-azidothymidine 5'-triphosphate (AZTMPPNP, 1e), the 5'-triphosphate analogue of AZTTP, is therefore both a substrate for and a potent inhibitor of HIV-1 RT with an observed Ki value of 87 nM.Further nitrogen substitution of the bridging oxygens in the phosphate chain decreases the inhibitory potency by approximately 10-fold as in the case of thymidine 5'-triphosphate (TMPNPNP, 1d).