Ester prodrugs of zidovudine

doi:10.1002/jps.2600790616

Journal of Pharmaceutical Sciences

Volume 79, Issue 6, June 1990, Pages 531-533

https://doi.org/10.1002/jps.2600790616 Get rights and content

Abstract

Ten novel ester prodrugs of zidovudine (azidothymidine; AZT) were synthesized with aliphatic acids (acetic–stearic), and the enzymatic regeneration of AZT from the prodrugs was investigated both in vitro and in vivo. The enzymatic hydrolysis rates of the AZT esters in the presence of mouse enzyme systems (plasma, liver, and intestine, and kidney) were highly dependent on the lengths of the acyl chains of the prodrugs. The caprate or caprylate of AZT showed the highest reactivity to three of the four enzyme systems; either the decrease or the increase in the acyl chain length resulted in the decrease of the reactivity to the enzymes. Zidovudine (AZT) and three of the prodrugs (acetate, caprate, and stearate) were administered to mice intraperitoneally, and the plasma concentrations of AZT and a corresponding prodrug were measured. The AZT concentrations in plasma following the acetate administration rapidly decreased with a half-life of 14.5 min. This tendency is similar to that shown in direct AZT administration. On the other hand, the concentrations following the caprate or stearate administration decreased slowly and were maintained for as long as 4 h after dosing. The prodrug concentrations in plasma after the prodrug administration were under the detection limit (0.01 μg/mL), except for acetate. The absence of the caprate and stearate in plasma may be attributed to the high hydrophobicity or favorable tissue distribution of the ester derivatives.

References and Notes (8)

N. Mir et al.
Lancet
(1988)
E. Dournon et al.
Lancet
(1988)
H. Mitsuya et al.
Proc. Natl. Acad. Sci. U.S.A.
(1985)
R.W. Klecker et al.
Clin Pharmacol. Ther.
(1987)

There are more references available in the full text version of this article.

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Once inside the cells, esterases will cleave the bond and release the active form of the drug. Such esters of AZT include steroid esters (Sharma et al., 1993), adamantane conjugates (Tsuzuki et al., 1994) and 5′-O-Aliphatic acids derivatives (Kawaguchi et al., 1990). Along the same line, the aforementioned ddI-Sq prodrug was tested on HIV-infected cells (Hillaireau et al., 2013) and found to decrease the ED50 (median effective dose) of the drug by 2- to 3-fold toward HIV-1-LAI infected peripheral blood mononuclear cells, and the ED90 (dose required for the effect in 90% of population) by up to 8-fold on ddI-resistant HIV-infected cells, compared to the free molecule.
In the context of the treatment of HIV/AIDS, many improvements have been achieved since the introduction of the combination therapy (HAART). Nevertheless, no cure for this disease has been so far possible, because of some particular features of the therapies. Among them, two important ones have been selected and will be the subject of this review. The first main concern in the treatments is the poor drug bioavailability, resulting in repeated administrations and therefore a demanding compliance (drug regimens consist of multiple drugs daily intake, and non-adherence to therapy is among the important reasons for treatment failure). A second important challenge is the need to target the drugs into the so-called reservoirs and sanctuaries, i.e. cells or body compartments where drugs cannot penetrate or are distributed in sub-active concentrations. The lack of antiviral action in these regions allows the virus to lie latent and start to replicate at any moment after therapy suspension. Recent drug delivery strategies addressing these two limitations will be presented in this review. In the first part, strategies to improve the bioavailability are proposed in order to overcome the absorption or the target cell barrier, or to extend the efficacy time of drugs. In the second section, the biodistribution issues are considered in order to target the drugs into the reservoirs and the sanctuaries, in particular the mononuclear phagocyte system and the brain.
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Zidovudine (AZT), as a typical member of the nucleoside analogues, was the first approved drug by food and drug administration (FDA) for the treatment of acquired immune deficiency syndrome (AIDS) which caused by human immunodeficiency virus (HIV), but its therapeutic effectiveness suffers from several clinical limitations, such as short half-life time, significant dose-related toxicity and drug resistance [9–11]. A variety of prodrugs of AZT have been reported to circumvent these limitations [12], including attachment of a chemical delivery system [13,14], esterification of the 5′-hydroxyl group of AZT [15–17], and incorporation of another anti-HIV moiety [18]. To overcome the limitations associated with the efficacy of AZT therapy, in an earlier study, our team synthesized a sustained-release prodrug of zidovudine by conjugating with methoxy poly(ethylene glycol) (mPEG, Mw: 2 kDa), and investigated its release kinetics in vitro and in vivo, as well as its anti-HIV activity [19].
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Since nucleosides exhibit only modest bioavailability [21], we prepared the prodrug molecules using amino and fatty acids to improve their bioavailability [22,23] and chemical stability. This was done to ensure enhanced cellular uptake and sustained release of drug molecule without compromising its properties [24–27]. The lead compound 4 and its prodrug 5 did not show any antiviral activity, whereas the prodrug 7 showed activity, albeit, too little against FCV and FHV.
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We have synthesized curcumin bioconjugates 2, 3, 4, 6, 8 and 10, wherein the phenolic hydroxyls and active methylene group on curcumin have been utilized. For the synthesis of compound 2 (Scheme 1), curcumin 1 was reacted with t-boc–N-trp–phe–COOH (indigenously synthesized) in 1:2 molar proportion using dicyclohexylcarbodiimide (DCC) coupling procedure in the presence of DMAP in anhydrous dichloromethane (DCM) to yield di-O-tryptophanylphenylalanine curcumin 2 in 53% yield [34]. Further, curcumin was reacted with decanoyl chloride and palmitoyl chloride in 1:2 molar proportion in the presence of DMAP in anhydrous pyridine to get the molecules 3 and 4 (Scheme 1) in 56% and 44% yield, respectively [35].
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It is known that the elimination of AZT from the body is very rapid and it has to be administered frequently in order to maintain therapeutic concentrations in the target organs and tissues, which increases its dose-dependent toxicity and side effects. In the early 1990s, some authors reported that a lower peak plasma level and a longer tmax of AZT were observed following the oral administration of a C18 ester prodrug [2,3]. Based on these findings, a series of prodrugs of AZT, including AZTC, were synthesized and studied in our laboratory [4,5].
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ArticlesEster prodrugs of zidovudine

Abstract

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Proc. Natl. Acad. Sci. U.S.A.

Clin Pharmacol. Ther.

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Ester prodrugs of zidovudine