Parent Nucleoside Research Articles

Retinoic acid conjugates as potential antitumor agents: synthesis and biological activity of conjugates with Ara-A, Ara-C, 3(2H)-furanone, and aniline mustard moieties.

In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.

Lymphatic Targeting of Anti-Human Immunodeficiency Virus Nucleosides: Pharmacokinetics of G′-Deoxy-2′,3′-Didehydrothymidine after Intravenous and Oral Administration of Dipalmitoylphosphatidyl Prodrug to Mice

The lymphatic system is a primary target for early anti-human immunodeficiency virus drug therapy. Strategies are currently being sought to enhance the delivery of nucleoside analogues such as 3′-deoxy-2′,3′-didehydrothymidine (stavudine; d4T) toward the lymph and lymph nodes. The purpose of this study was to synthesize dipalmitoylphosphatidyl-d4T (DPP-d4T) as a lipophilic prodrug of d4T and to evaluate the lymphatic distribution of d4T following administration of d4T and DPP-d4T to mice. The pharmacokinetics of d4T were characterized following administration of a single intravenous or oral dose of 50 mg kg−1d4T and an equimolar dose (214 mg kg−1) of DPP-d4T. Concentrations of d4T in serum and lymph nodes were determined by HPLC. Following administration of d4T, the distribution of d4T into lymph nodes was rapid with maximum concentrations observed within 5 min after dosing. The AUC and half-life values of d4T in three groups of lymph nodes were similar to those in serum. Administration of DPP-d4T resulted in significantly lower concentrations of d4T in serum and lymph nodes. Approximately 67% of the intravenously administered DPP-d4T was biotransformed to parent compound. The apparent oral bioavailability of DPP-d4T was low. While the phospholipid prodrug did not increase d4T concentrations in the lymph nodes, it did provide an extended release of the parent nucleoside, resulting in sustained concentrations of d4T.

Probing the mechanism of action and decomposition of amino acid phosphomonoester amidates of antiviral nucleoside prodrugs.

The decomposition pathways in peripheral blood mononuclear cells (PBMCs) and the in vitro anti-HIV-1 activity of the structurally similar 3'-azido-3'-deoxythymidine (AZT) phosphoramidates 1-6 and 3'-fluoro-3'-deoxythymidine (FLT) phosphoramidates 7-10 are reported. The AZT phosphoramidates exhibited no cytotoxicity toward CEM cells at concentrations as high as 100 microM, whereas the FLT phosphoramidates 9 and 10 had CC50 values of 95.6 and 35.1 microM, respectively. All 10 compounds exhibited no cytotoxicity toward PBMCs at concentrations as high as 100 microM and were effective at inhibiting viral replication. In particular, the AZT phosphomonoester amidate 4 displayed comparable antiviral activity to the parent nucleoside analog AZT. Mechanistic studies on the amino acid carbomethoxy ester phosphomonoester amidates revealed that their decomposition pathway differs from that of amino acid carbomethoxy ester aryl phosphodiester amidates of nucleotide prodrugs. AZT phosphomonoester amidates are internalized by lymphocytes to the same extent as AZT by a nonsaturable process. In lymphocytes, the amino acid carbomethoxy ester phosphomonoester amidates of AZT are not significantly metabolized to either AZT or the mono-, di-, or triphosphate of AZT. The amount of active anabolite, AZT-5'-triphosphate, formed in PBMCs incubated with the AZT phosphomonoester amidates 3 and 4 was 2- and 3-fold less than that observed after treatment with AZT, respectively. In contrast, FLT phosphomonoester amidates are rapidly converted to FLT-5'-monophosphate by a process that is antagonized by the corresponding AZT derivative 4. These results suggest that the metabolism of aromatic amino acid carbomethoxy ester phosphomonoester amidate nucleotide prodrugs by PBMCs does not require prior conversion to the corresponding carboxylic acid before proceeding to P-N bond cleavage.

Biotransformation and pharmacokinetics of prodrug 9-( β- d-1,3-dioxolan-4-yl)-2-aminopurine and its antiviral metabolite 9-( β- d-1,3-dioxolan-4-yl)guanine in mice

9-( β- d-1,3-Dioxolan-4-yl)guanine (DXG) exhibits potent antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. However, since DXG possesses limited aqueous solubility, a more water soluble prodrug of DXG, 9-( β- d-1,3-dioxolan-4-yl)-2-aminopurine (APD), was synthesized. The purpose of this study was to characterize the pharmacokinetics of APD and its antiviral metabolite DXG in mice. Female NIH-Swiss mice were administered 100 mg/kg APD intravenously or orally. Serum, brain and liver were collected at selected times following prodrug administration and concentrations of APD and DXG were determined by HPLC. APD was efficiently converted to parent nucleoside DXG following both intravenous and oral administration. Biotransformation of APD to DXG likely occurs in the liver and is mediated by xanthine oxidase. Similar pharmacokinetic profiles for DXG were observed following either route of administration in serum, liver and brain. These results demonstrate that APD appears to be a promising prodrug for the delivery of DXG.

Lymphatic targeting of anti-HIV nucleosides: distribution of 2′,3′-dideoxyinosine after intravenous and oral administration of dipalmitoylphosphatidyl prodrug in mice

In the search for prodrugs of 2′,3′-dideoxyinosine (ddI) with potential for improving the delivery of the nucleoside analogue to the lymphatic system, we synthesized dipalmitoylphosphatidyl-2′,3′-dideoxyinosine (DPP-ddI) and its pharmacokinetics were investigated in mice. The disposition of ddI in plasma and lymph nodes was examined following intravenous and oral administration of parent nucleoside (100 mg/kg) and DPP-ddI (400 mg/kg, equivalent to 100 mg/kg of ddI). Concentrations of ddI were determined by HPLC. Pharmacokinetic parameters were estimated by area/moment analysis. Intravenous administration of DPP-ddI resulted in a pattern of lower peak concentrations of ddI and more sustained exposure of parent nucleoside in plasma and lymph nodes compared to administration of the parent nucleoside. Both ddI and DPP-ddI yielded similar AUC values in lymph nodes. Oral administration of the prodrug resulted in lower concentrations and AUC values of ddI in plasma and lymph nodes when compared to administration of the parent nucleoside. The bioavailability of ddI following ddI and DPP-ddI administration was 15 and 8%, respectively. The results of the present study demonstrate that DPP-ddI administered intravenously shows potential for targeting and sustaining level of ddI in the nodular lymphatic tissues.

High-performance liquid chromatographic determination of (-)-beta-D-2-aminopurine dioxolane and (-)-beta-D-2-amino-6-chloropurine dioxolane, and their metabolite (-)-beta-D-dioxolane guanine in monkey serum, urine and cerebrospinal fluid.

(-)-beta-D-2-Aminopurine dioxolane (APD), (-)-beta-D-2-amino-6-chloropurine dioxolane (ACPD) and dioxolane guanine (DXG) are nucleoside analogues possessing potent activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) in vitro. APD and ACPD are metabolized in vivo to yield DXG. Reversed-phase HPLC analytical methodologies were developed for the simultaneous determination of APD and DXG, and for ACPD and DXG in monkey serum, urine and cerebrospinal fluid (CSF). 2-Fluoro-2',3'-dideoxyinosine (FDDI) served as the internal standard. The extraction recoveries of the nucleoside analogues from serum samples were similar, averaging approximately 90%. The limit of quantitation of the analytical method for serum samples was 0.1 microg/ml for DXG, and 0.25 microg/ml for APD and ACPD. The intra- and inter-day relative standard deviations for each compound at low, medium and high nucleoside concentrations were less than 9.0%. The accuracy of the assay methods was greater than 90% for prodrugs and parent compound. Similar results were observed with urine and CSF samples. Thus, these methods provide sensitive, accurate and reproducible determination of the prodrugs and parent nucleoside in biological samples.

Synthesis and Evaluation of Some Symmetrical Phosphate Dimer Derivatives of 3′-Modified Nucleosides as Potential anti-HIV Agents

Novel symmetrical nucIeotide-(5′,5′)-dimers of 3′-O-acetylthymidine, 3′-O-methylthymidine, 3′-O-ethylthymidine, 3′-O-n-propylthymidine and 3′-azido-3′-deoxythymidine (AZT) were synthesized as membrane soluble pro-drugs. These were prepared using phosphorodichloridate chemistry and were characterised by spectroscopic and analytical data. In-vitro evaluation of the derivatives in cells acutely infected with the human immunodeficiency virus (HIV-1) demonstrated a range of activities. These derivatives were generally found to display poor inhibition of HIV proliferation. Derivatives containing AZT moieties were found to be potent, but such compounds were less active than the parent nucleoside. The data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the activity.

Antitrypanosomal activity of purine nucleosides can be enhanced by their conversion to O-acetylated derivatives.

Fifteen purine nucleosides and their O-acetylated ester derivatives were examined for in vitro antitrypanosomal activity against the LAB 110 EATRO isolate of Trypanosoma brucei brucei and two clinical isolates of Trypanosoma brucei rhodesiense. Initial comparisons of activity were made for the LAB 110 EATRO isolate. Three nucleoside analogs exhibited no significant activity (50% inhibitory concentrations [IC50s] of > 100 microM), whether they were O acetylated or unacetylated; three nucleosides showed almost equal activity (IC50s of < 5 microM) for the parent compound and the O-acetylated derivative; nine nucleosides showed significantly improved activity (> or = 3-fold) upon O acetylation; of these nine analogs, six displayed activity at least 10-fold greater than that of their parent nucleosides. The most significant results were those for four apparently inactive compounds which, upon O acetylation, displayed IC50s of < or = 25 microM. When the series of compounds was tested against T. brucei rhodesiense isolates (KETRI 243 and KETRI 269), their antitrypanosomal effects were comparable to those observed for the EATRO 110 strain. Thus, our studies of purine nucleosides have determined that O acetylation consistently improved their in vitro antitrypanosomal activity. This observed phenomenon was independent of their cellular enzyme targets (i.e., S-adenosylmethionine, polyamine, or purine salvage pathways). On the basis of our results, the routine preparation of O-acetylated purine nucleosides for in vitro screening of antitrypanosomal activity is recommended, since O acetylation transformed several inactive nucleosides into compounds with significant activity, presumably by improving uptake characteristics. O-acetylated purine nucleosides may offer in vivo therapeutic advantages compared with their parent nucleosides, and this possibility should be considered in future evaluations of this structural class of trypanocides.

Phosphoramidate derivatives of 2′,3′-didehydro-2′,3′-dideoxyadenosine [d4A] have markedly improved anti-HIV potency and selectivity

New 5′-phosphate derivatives of the nucleoside analogue d4A were prepared as potential membrane-soluble prodrugs of the free nucleotide. The anti-viral potency and selectivity of the derivatiyes is markedly increased by comparison to the parent nucleoside analogue. The new analogues show particular promise for further pre-clinical development.

Pharmacokinetics of (-)-beta-D-2-aminopurine dioxolane and (-)-beta-D-2-amino-6-chloropurine dioxolane and their antiviral metabolite (-)-beta-D-dioxolane guanine in rhesus monkeys.

(-)-beta-D-2-Aminopurine dioxolane (APD) and (-)-beta-D-2-amino-6-chloropurine dioxolane (ACPD) are recently synthesized dioxolanylpurine nucleoside derivatives being developed as potential prodrugs for the antiviral nucleoside analog (-)-beta-D-dioxolane guanine (DXG). In vitro, APD and ACPD are converted to DXG by xanthine oxidase and adenosine deaminase, respectively. The purpose of this study was to evaluate the preclinical pharmacokinetics of APD and ACPD and their potential for generating sustained levels of the parent nucleoside, DXG, in rhesus monkeys following oral administration. Both nucleoside derivatives were rapidly absorbed, with similar peak concentrations achieved within 1 h after administration. However, concentrations of APD were more markedly sustained than those of ACPD. Both prodrugs yielded DXG, but significantly higher serum concentrations of DXG and area under the concentration-time curve values were observed following administration of APD. In addition, APD produced higher concentrations of prodrug and DXG in cerebrospinal fluid than did ACPD. Thus, the results of this pharmacokinetic study suggest that APD is likely to serve as a better prodrug of DXG and should be considered for clinical trials for antiviral therapy against human immunodeficiency virus and hepatitis B virus.

Physicochemical Properties, Bioconversion and Disposition of Lipophilic Prodrugs of 2′,3′-Dideoxycytidine

Lipophilic prodrugs of 2′,3′-dideoxycytidine (ddC), 4,5′-diacetyI-ddC (DAC), 4,5′-ditrimethylacetyl-ddC (DTMAC), 4,5′-dicyclopentylpropionyl-ddC (DCYPP) and 5′-cholesteryl-ddC (CHOL), were evaluated for their utility in improving brain delivery of the parent nucleoside. The lipophilicity of the prodrugs was greater, compared to ddC., with partition coefficient values increasing from 0.03 for ddC to 0.37,28, 63 and 483 for DAC., DTMAC., DCYPP and CHOL., respectively. Aqueous solubility was decreased proportionally to the increase in lipophilicity. Bioconversion studies were performed in phosphate buffer (pH 7.4), human serum, mouse serum, and mouse brain and liver homogenates. Whereas CHOL was stable in vitro in all media, DAC., DTMAC and DCYPP exhibited stability only in buffer, indicating that the hydrolytic reaction for these compounds was, predominately, enzymatically triggered. DCYPP was rapidly hydrolysed in mouse serum and liver and brain homogenates with degradation half-life values of 0.04, 0.35 and 0.34 h respectively. DAC had a longer half-life in mouse serum than did DTMAC (0.82 h vs. 0.38 h), however, in mouse brain homogenate DTMAC (t1/2=3.9 h) was more stable than DAC (t1/2= 1.6 h). Both of these pro-drugs were rapidly metabolized in the mouse liver homogenate with half-life values of 0.36 h for DAC and 0.23 h for DTMAC. In-vivo studies performed for ddC., DAC and DTMAC in mice showed that the relative brain exposure (re) of ddC was not improved by administering the prodrugs. DTMAC yielded a re value of 0.023 which was similar to that for ddC (re = 0.028), while no ddC was detected in brain after DAC administration. Thus, although all of the prodrugs were more lipophilic than ddC., delivery of ddC to the brain was not enhanced in vivo.

Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells

New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble pro-drugs of the bio-active free nucleotide. Some of the derivatives appear to have enhanced antiviral efficacy relative to the parent nucleoside analogue. Moreover, the derivatives appear to by-pass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. The new analogues show particular promise for further pre-clinical development.

PCILO studies on anti-AIDS agents: conformation of ddG and ddAPR

Abstract Conformational preferences of two anti-AIDS agents: 2′,3′-dideoxyguanosine (ddG) and 2′,3′-dideoxy-2,6-diaminopurine riboside (ddAPR) have been investigated by using the semi-empirical quantum mechanical PCILO method. The computations have been carried on these anti-AIDS agents having both C2′-endo and C3′-endo sugar puckers as well as their respective parent molecules, guanosine (G) and 2,6-diaminopurine riboside (APR). The results obtained exhibit a remarkable similarity in the conformation of these anti-AIDS agents and their parent nucleosides. The important biological significance of this result has been discussed in the light of our earlier results on the conformation on azidothymidine (AZT) which is the most widely used anti-AIDS drug throughout the world.

Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite.

New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.

Decomposition pathways and in vitro HIV inhibitory effects of isoddA pronucleotides: toward a rational approach for intracellular delivery of nucleoside 5'-monophosphates.

The decomposition pathways and kinetics in various biological media and the in vitro anti-HIV-1 and anti-HIV-2 activities of four derivatives of the 5'-mononucleotide of isoddA incorporating carboxylate esterase-labile transient phosphate protecting groups are reported and compared: namely, two mononucleoside aryl phosphoramidate derivatives 1a,b and two mononucleoside phosphotriester derivatives incorporating two S-acyl-2-thioethyl groups 2a,b. All four compounds show better antiviral activity, compared to the parent nucleoside analog isoddA. The results highlight that both types of compounds act as pronucleotides, i.e. they exert their antiviral effect via intracellular delivery of the 5'-mononucleotide of isoddA. The results may give insights for the design of new more efficient pronucleotides.

5′,5′‐di‐O‐nucleosyl‐O′‐benzylphosphotriesters as potential prodrugs of 3′‐azido‐2′,3′‐dideoxythymidine‐5′‐monophosphate

AbstractThe synthesis of 5′,5′‐O‐di‐(3′‐azido‐2′,3′‐dideoxythymidinyl)‐O′‐benzylphosphotriesters 1 as potential prodrugs of nucleoside monophosphates is described. The concept is applied to the antiretroviral nucleoside analog 3′‐azido‐2′,3′‐deoxythymidine (AZT) 4. All derivatives 1 were synthesized by reaction of the tetra‐n‐butylammonium salt of di‐AZT‐phosphate 2b with different benzyl bromides or ‐chlorides 9. Compound 2b was obtained by a combination of phosphoamidite/H‐phosphonate chemistry, subsequent oxidation to 2a, and cation exchange. The partition coefficients of 1 in an 1‐octanol/water mixture show that all compounds exhibit a much higher lipophilicity than the parent nucleoside AZT (4). It was also shown, that 1 decomposes spontaneously under mild aqueous basic conditions (phosphate buffer (pH 7.5) and RPMI culture medium containing heat‐deactivated fetal calf serum) releasing selectively the di‐AZT phosphate anion 2. The half‐lives of 1 could be adjusted within a wide range by changing the ring substituents of the benzyl group. Additionally, the mechanism of hydrolysis varies if the substituent is changed from a donor to an acceptor one. The described phosphotriesters 1 exhibit considerable antiviral activity in HIV‐1‐ and HIV‐2‐infected CEM/O cells, whereas no activity was detected in the HIV‐2‐infected thymidine kinase‐deficient CEM cell line. On the other hand, we could not detect any cytotoxicity of the described phosphotriesters. Consequently, compounds 1 should act as prodrugs or depot forms at least of antiviral nucleoside analogs.

Increase of the anti-HIV activity of D4T in human T-cell culture by the use of the sate pronucleotide approach

The bis( S-acetyl-2-thioethyl) phosphotriester derivative of 2′,3′-didehydro-2′,3′-dideoxythymidine has been synthesized and evaluated for its inhibitory effects on the replication of HIV-1 in several cell culture systems. This pronucleotide showed potent anti-HIV activity and proved to be significantly superior to the parent nucleoside with regard to the antiviral efficiency.

Lymphatic Targeting of anti-HIV Nucleosides: Distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) after Administration of Dipalmitoylphosphatidyl Prodrugs to Mice

Human immunodeficiency virus appears to be proliferating within the lymphatic system throughout the period of clinical latency. Targeting of anti-HIV compounds to the lymphatic tissue may therefore provide therapeutic benefits. The purpose of this investigation was to determine the distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) in lymph nodes in a mouse model after administration of the lipophilic prodrugs dipalmitoylphosphatidyl-azidodeoxythymidine (DPP-AZT) and dipalmitoylphosphatidyl-azidodideoxyuridine (DPP-AZdU). Mice received 50 mg kg−1 of parent nucleoside and 164 mg kg−1 of DPP-AZT (equivalent to 50 mg kg−1 AZT) intravenously or orally and 180mg kg−1 DPP-AZdU (equivalent to 50 mg kg−1 AZdU) orally. Serum, neck, axillary and mesenteric lymph nodes were collected at selected times and AZT and AZdU concentrations were determined by HPLC. The disposition of AZT and AZdU in serum and lymph nodes was significantly altered after intravenous and oral administration of DPP-AZT and oral administration of DPP-AZdU when compared to that after administration of parent nucleoside. Lower peak concentrations of AZT and AZdU were observed in serum and lymph nodes after administration of the phospholipid prodrugs. However, DPP-AZT and DPP-AZdU produced consistently higher concentrations of AZT and AZdU, respectively, 2-3 h after prodrug administration. Half-life values for both nucleosides in serum and lymph nodes were significantly greater after prodrug administration. Greater AUC values for nucleosides were noted in neck (AZT and AZdU) and mesenteric (AZT) lymph nodes after administration of prodrugs compared with values obtained for parent drugs. Furthermore, relative lymph node exposure to AZT and AZdU in the lymph nodes was greater after administration of prodrug than after administration of parent compound. Thus, DPP-AZT and DPP-AZdU show potential as useful prodrugs for the delivery of AZT and AZdU to the lymphatic system.

Synthesis of nucleoside 3′-phosphonates via 3′-keto nucleosides

Nucleophilic addition of diethyl phosphite anion to several 2′- or 3′-keto nucleosides results in an efficient synthesis of 2′-hydroxy-2′-phosphono- or 3′-hydroxy-3′-phosphononucleosides. The stereochemistry of one such adduct, 3′α-diethylphosphono-3′β-hydroxy-5′-O-tritylthymidine, was determined by single crystal diffraction analysis. When the 5′-hydroxyl group is protected with groups that are not sterically demanding, the 3′ geminal hydroxy phosphonates undergo radical deoxygenation under modified Barton conditions to afford the reduced compounds in good yields. Removal of the remaining hydroxyl protecting groups, and hydrolysis of the phosphonate acid esters, then gives the parent nucleoside 3′-phosphonic acids.

Bis(S-Acyl-2-thioethyl)esters of 2',3'-Dideoxyadenosine 5'-Monophosphate Are Potent Anti-HIV Agents in Cell Culture

Abstract It is shown that ddA bis(SATE)phosphotriesters have potent anti-HIV activity in cell culture. Thus, compared with the parent nucleoside, a decrease of 3 or 4 orders of magnitude was observed in the EC50 values for the bis(S-acetyl-2-thioethyl)phosphotriester derivative, which makes this compound as active as AZT.