Novel approaches for designing 5 '-O-ester prodrugs of 3'-azido-2 ',3 '-dideoxythymidine (AZT)

3'-Azido-2',3'-dideoxythymidine (AZT, 1, zidovudine, Retrovir(TM)) is used to treat patients with human immunodeficiency virus (HIV) infection. AZT, a fter conversion to AZT-5'-triphosphate (ATT-TP) by cellular enzymes, inhibi ts HIV-reverse transcriptase (HIV-RT). The major clinical limitations of AT T are due to clinical toxicities that include bone marrow suppression, hepa tic abnormalities and myopathy, absolute dependence on host cell kinase-med iated activation which leads to low activity, limited brain uptake, a short half-life of about one hour in plasma that dictates frequent administratio n to maintain therapeutic drug levels, low potential for metabolic activati on and/or high susceptibility to catabolism, and the rapid development of r esistance by HIV-1. These limitations have prompted the development of stra tegies for designing prodrugs of AZT. A variety of 5'-O-substituted prodrug s of AZT constitute the subject of this review. The drug-design rationale o n which these approaches are based is that the ester conjugate will be conv erted by hydrolysis and/or enzymatic cleavage to AZT or its 5'-monophosphat e (AZT-MP). Most prodrug derivatives of AZT have been prepared by derivatiz ation of AZT at its 5'-O position to provide two prominent classes of compo unds that encompass: A) 5'-O-carboxylic esters derived from 1) cyclic 5'-O- carboxylic acids such as steroidal 17 beta-carboxylic acids, 1-adamantaneca rboxylic acid, bicyclam carboxylic acid derivatives, O-acetylsalicylic acid , and carbohydrate derivatives, 2) amino acids, 3) 1,4-dihydro-1-methyl-3-p yridinylcarboxylic acid, 4) aliphatic fatty acid analogs such as myristic a cid containing a heteroatom, or without a heteroatom 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 foscarn et derivatives, 2) a variety of phosphotriesters that include dialkylphosph otriesters, diarylphosphotriesters, glycolate and lactate phosphotriesters, phosphotriester approaches using simultaneous enzymatic and chemical hydro lysis of bis(4-acyloxybenzyl) esters, bis(S-acyl-2-thioethyl) (SATE) esters , cyclosaligenyl prodrugs, glycosyl phosphotriesters, and steroidal phospho triesters, 3) phosphoramidate derivatives, 4) dinucleoside phosphate deriva tives that possess a second anti-HIV moiety such as AZT-P-ddA, AZT-P-ddl, A ZTP2AZT, AZTP2ACV), and 5) 5'-hydrogen phosphonate and 5'-methylene phospho nate derivatives of AZT. In these prodrugs, the conjugating moiety is linke d to AZT via a 5'-O-ester or 5'-O-phosphate group. 5'-O-Substituted AZT pro drugs have been designed with the objectives of improving anti-HIV activity , enhancing blood-brain barrier penetration, modifying pharmacokinetic prop erties to increase plasma half-life and improving drug delivery with respec t to site-specific targeting or drug localization. Bypassing the first phos phorylation step, regulating transport and conferring sustained release of AZT prolong its duration of action, decrease toxicity and improve patient a cceptability. The properties of these prodrugs and their anti-HIV activitie s are now reviewed.