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Novel Approaches for Designing 5'-O-Ester Prodrugs of 3'-Azido-2'3'-dideoxythymidine (AZT)

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Abstract:

3'-Azido-2'3'-dideoxythymidine (AZT, 1, zidovudine, RetrovirTM) is used to treat patients with human immunodeficiency virus (HIV) infection. AZT, after conversion to AZT-5'-triphosphate (AZT-TP) by cellular enzymes, inhibits HIV-reverse transcriptase (HIV-RT). The major clinical limitations of AZT are due to clinical toxicities that include bone marrow suppression, hepatic abnormalities and myopathy, absolute dependence on host cell kinase-mediated activation which leads to low activity, limited brain uptake, a sort half-life of about one hour in plasma that dictates frequent administration to maintain therapeutic drug levels, low potential for metabolic activation and/or high susceptibility to catabolism, and the rapid development of resistance by HIV-1. These limitations have prompted the development of strategies for designing prodrugs of AZT. A variety of 5'-O-substituted prodrugs of AZT constitute the subject of this review. The drugdesign rationale on which these approaches are based is that the ester conjugate will be converted by hydrolysis and/or enzymatic cleavage to AZT or its 5'-monophosphate (AZT-MP). Most prodrug derivatives of AZT have been prepared by derivatization of AZT at its 5'-O position to provide two prominent classes of compounds that encompass: A) 5'-O-carboxylic esters derived from 1) cyclic 5'-O-carboxylic acids such as steroidal 17b-carboxylic acids, 1-adamantanecarboxylic acid, bicyclam carboxylic acid derivatives, O-acetylsalicylic acid, and carbohydrate derivatives, 2) amino acids, 3) 1,4-dihydro-1-methyl-3-pyridinylcarboxylic acid, 4)such as stearic acid, and 5) long chain polyunsaturated fatty acid analogs such as retinoic acid, and B) masked phosphates such as 1) phosphodiesters that include monoalkyl or monoaryl phosphate, carbohydrate, ether lipid, ester lipid, and foscarnet derivatives, 2) a variety of phosphotriesters that include dialkylphosphotriesters, diarylphosphotriesters, glycolate and lactate phosphotriesters, phosphotriester approaches using simultaneous enzymatic and chemical hydrolysis of bis(4-acyloxybenzyl) esters, bis (S-acyl-2-thioethyl) (SATE) esters, cyclosaligenyl prodrugs, glycosyl phosphotriesters, and steroidal phosphotriesters, 3) phosphoramidate derivatives, 4) dinucleoside phosphate derivatives that possess a second anti-HIV moiety such as AZT-P-ddA, AZT-Pddl, AZTP2AZT, AZTP2ACV), and 5) 5'-hydrogen phosphonate and 5'methylene phosphonate derivatives of AZT. In these prodrugs, the conjugating moiety is linked to AZT via a 5'O-ester or 5'-O-phosphate group. 5'-O-Substituted AZT prodrugs have been designed with the objectives of improving anti-HIV activity, enhancing blood-brain barrier penetration, modifying pharmacokinetic properties to increase plasma half-life and improving drug delivery with respect to site-specific targeting or drug localization. Bypassing the first phosphorylation step, regulating transport and conferring sustained release of AZT prolong its duration of action, decrease toxicity and improve patient acceptability. The properties of these prodrugs and their anti-HIV activities are now reviewed.

Keywords: (Acyloxy) Alkyl; (HIV) infection; 1,4-Dihydro-1-methyl-3-[(pyridylcarbonyl)oxy]ester; 1,4-dihydro-1-methyl-3-pyridinylcarboxylic acid; 2'3'-Dideoxynucleosides; 3'-Azido-2'3'-dideoxythymidine (AZT); 5'-O-Aliphatic derivatives of AZT; 5'-O-Ester prodrugs; 5'-O-Myristoyl derivatives of AZT; AZT Masked phosphate prodrugs; AZT monophosphate, diphosphate and triphosphate di; Adamantane Conjugates; Amino acid ester; Aryl phosphate trimesters of AZT; Aspirin (O-acetylsalicylic acid) prodrug of AZT; Bicyclam-AZT Conjugates; Bis (S-Acyl-2-thioethyl) (SATE) esters of AZT-MP [; Carbohydrate Derivatives; Carbohydrate Ester Derivatives; Carboxylic Esters (13-64); Cyclosaligenyl-AZT; Dialkyl phosphotriester derivatives; Diaryl phosphotriester derivatives; Dinucleoside phosphate derivatives; Ether Lipids (Els); Foscarnet derivatives of AZT; Glycolate and lactate phosphotriesters; Immunodeficiency virus; Inhibitors of viral reverse transcriptase (RT); Long chain polyunsaturated fatty acid analogs; Monoalkyl or Monoarylphosphate derivatives of AZT; Phosphodiesters of AZT; Phosphoramidate derivatives; Phosphormaidate derivatives; Phosphotriesters; Polyunsaturated aliphatic acid; Steroid Esters; Steroidal phosphotriester derivatives; cyclic 5'-O-carboxylic acids; dinucleoside phosphate derivatives

Document Type: Review Article

DOI: https://doi.org/10.2174/0929867003374372

Publication date: 2000-10-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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