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" Evaluation of myristic acid analogs and 5'-O-ester prodrugs of thymidine (dThd), 3'-azido-3'-deoxythymidine (AZT) and 3'-fluoro-3'-deoxythymidine (FLT) "
K. Parang
L. I. K. Wiebe, E. E.
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Latin Dissertation
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English
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| Record Number
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1113330
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TLpq304382559
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| Main Entry
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K. Parang
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L. I. K. Wiebe, E. E.
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| Title & Author
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Evaluation of myristic acid analogs and 5'-O-ester prodrugs of thymidine (dThd), 3'-azido-3'-deoxythymidine (AZT) and 3'-fluoro-3'-deoxythymidine (FLT)\ K. ParangL. I. K. Wiebe, E. E.
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| College
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University of Alberta (Canada)
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| Date
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1997
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1997
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| Degree
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Ph.D.
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| Page No
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288
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| Abstract
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A series of prodrugs of zidovudine (AZT) and alovudine (FLT) has been synthesized in an effort to enhance their anti-HIV-1 activity, duration of action, lipophilicity, uptake by HIV-1 infected cells, delivery to the central nervous system and liver, and plasma half-life. Some of the other goals of this approach were to prevent opportunistic fungal infections, to improve drug transport, to reduce toxicity, and to overcome drug resistance. The syntheses and pharmacological evaluation of myristic acid analogs and 5-O-myristoyl analogue derivatives of nucleosides (AZT, FLT, dThd) have been investigated. The myristic acid analogs were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans), filamentous fungi (Aspergillus niger) and viruses (human immunodeficiency virus, hepatitis B virus, and duck hepatitis B virus). Anti-HIV-1 activities of 5-O-myristoyl analogs of thymidine (81a-h), zidovudine (82a-87) and alovudine (91a-93) analogs were determined against HIV-infected CD4 lymphocytes. All the prodrugs were more lipophilic than the parent compounds dThd (8), AZT (6), and FLT (7). The structures of the 5-O-myristoylthymidine analogs (81a-h) were optimized using molecular mechanics (MM force field), and semi-empirical quantum mechanics (PM3), calculations. A quantitative structure-activity relationship (QSAR) regression equation was developed, based on the optimized structures and anti-HIV data using the SciQSAR computational program, which showed that Log P was a determinant of anti-HIV activity. All of the AZT and FLT prodrugs (82a-87, 91a-93) exhibited potent activity against HIV. 3-Azido-5-O-(4-oxatetradecanoyl)-2,3 -deoxythymidine (82c) (EC{50} = 1.4 nM) showed greater activity than AZT (6) (EC{50} = 10.0 nM) against HIV-infected CD4 lymphocytes in the CEM-SS cell line. The antiviral efficacy of some analogs were evaluated using a hepatitis virus B (HBV) DNA-transfected cell line 2.2.15 in vitro. The stability of 5-O-esters of dThd, AZT and FLT were determined following their in vitro incubation in the presence of porcine liver esterase, rat plasma and rat brain homogenate at 37C. Subsequent quantitative HPLC analyses indicated that these agents had a wide range of stability. For example, these myristoyl analog esters were cleaved by porcine liver esterase with a usdt\sb{1/2}usd in the range of 1.9 to 80.4 min. The pharmacokinetics of 3-azido-2,3-dideoxythymidine (6, usd\beta\ t\sb{1/2}usd = 112.5 min; AUC = 29.12 2.92 mumol.g.min; CL = 10.47 1.05 mL min.kg and ()-3-azido-2,3- dideoxy-5-O-(2-bromomyristoyl)thymidine (85b, usd\beta\ t\sb{1/2}usd = 428.5 min; AUC = 17.34 4.69 mumol.g.min; CL = 17.58 4.76 mL min.kg were determined in male uninfected Balb/c mice (25-30 g). The in vivo results acquired indicate that the ester (85b) was rapidly converted to AZT in vivo. The biodistribution studies using selected compounds (6, 68c, 85b) demonstrated that 85b provided AZT brain and liver concentrations greater than those measured following an equimolar doses of AZT. However, 85b provided lower plasma levels of AZT, than observed after AZT administration. Mean brain/blood concentration ratios for AZT after prodrug ester administration (0.16 0.03) were greater than those obtained after AZT injection (0.06 0.001). It is concluded that these analogs are potential prodrugs for the treatment of AIDS. This pharmaceutical approach would be beneficial for the efficient treatment of CNS and liver infections by human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV).
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anti-HIV
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Health and environmental sciences
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immune deficiency
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Pharmacology
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Pure sciences
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