Chalcogenium-AZT Derivatives: A Plausible Strategy To Tackle The RT-Inhibitors-Related Oxidative Stress While Maintaining Their Anti- HIV Properties.

BACKGROUND: This study presents the synthesis and multi-target behavior of the new 5'-hydroxy-3-(chalcogenyl-triazoyl)-thymidine and the biological evaluation of these compounds as antioxidant and anti-HIV agents. OBJECTIVE: Antiretroviral therapy induces oxidative stress. Based on this, this manuscript's main objective is to prepare compounds that combine anti-HIV and antioxidant activities. METHODS: The compounds were prepared from commercially available AZT through a copper-catalyzed Huisgen 1,3-dipolar cycloaddition exploiting the AZT azide group and chalcogenyl alkynes. RESULTS: The chalcogenium-AZT derivatives were obtained in good yields via click chemistry. The compounds evaluated showed antioxidant and anti-HIV activity. Additionally, in vivo toxicity of this class of compounds was also evaluated. The representative nucleoside did not change the survival, behavior, biochemical hepatic, or renal markers compared to the control mice. CONCLUSION: Data suggest the feasibility of modifying the AZT nucleus with simple organohalogen fragments, exploring the reactivity of the azide group via 1,3-dipolar Huisgen cycloaddition reaction. The design of these new compounds showed the initially desired biological activities.

Zidovudine Glycosylation by Filamentous Fungi Leads to a Better Redox Stability and Improved Cytotoxicity in B16F10 Murine Melanoma Cells.

BACKGROUND: The strategic development of therapeutic agents, capable of being targeted at their active sites, has been a major goal in treatment of cancer. The delivery of drugs for tumors has as its main challenge the development of safe and effective drugs, since the goal of chemotherapy is to eliminate the tumor completely without affecting healthy cells. The aim of present study was to investigate the antioxidant, anticancer activities of zidovudine and its α-O-glycosylated derivative obtained by biosynthesis of a filamentous fungi, Cunninghamela echinulata. METHODS: An evaluation of the cytotoxic potential of zidovudine and its α-O-glycosylated was performed in fibroblasts and melanoma cells by the tetrazolium reduction method (MTT) and the antioxidant activity of this derivative was observed. RESULTS: The antioxidant activity of zidovudine demonstrated an electrochemical oxidation potential of 0.91V, while the α-O-glycosylated derivative did not exhibit any antioxidant activity. The zidovudine exhibited low cytotoxicity for melanoma and fibroblast cells, while the α-O-glycosylated derivative presented better cytotoxicity on melanoma cells at a concentration of 10mg. mL-1. CONCLUSION: This study demonstrates the specific cytotoxicity of the glycoconjugate and suggests that glycosylation by biosynthesis can be a useful strategy for obtaining new anticancer compounds.

In situ microemulsion-gel obtained from bioadhesive hydroxypropyl methylcellulose films for transdermal administration of zidovudine.

This study aims to develop in situ microemulsion-gel (ME-Gel) obtained from hydroxypropyl methylcellulose (HPMC) films for transdermal administration of Zidovudine (AZT). Firstly, HPMC films containing propylene glycol (PG) and eucalyptus oil (EO) were obtained and characterized. Later, a pseudo-ternary phase diagram composed of water, EO, tween 80 and PG was obtained and one microemulsion (ME) with a similar proportion of the film components was obtained. ME was transformed in ME-Gel by the incorporation of HPMC. Finally, HPMC films were hydrated with Tween 80 solution to yield in situ ME-Gel and its effect on AZT skin permeation was compared with HPMC film hydrated with water (F5hyd). The results showed that the ME and ME-Gel presented a droplet size of 16.79 and 122.13 µm, respectively, polydispersity index (PDI) < 0.39 and pH between 5.10 and 5.40. The incorporation of HPMC resulted in viscosity about 2 times higher than the use of ME. The presence of AZT did not alter the formulation properties. The in situ ME-Gel promoted a two-fold increase in the permeated amount of AZT compared to F5hyd. The results suggest that it was possible to obtain an ME-Gel in situ from HPMC films and that its effect on transdermal permeation of AZT was significant.

Human serum albumin binding of novel antiretroviral nucleoside derivatives of AZT.

The binding of novel nucleoside derivatives (2-7) to the Human Serum Albumin (HSA) was studied using zidovudine (AZT), as standard compound. The applicability of two different techniques to separate unbound drug from drug-protein complex was analyzed: the gel filtration and ultrafiltration methods. Ultrafiltration was found to be an adequate procedure for the separation of unbounded drug from the drug-protein complex. Incubation temperature ranging from 0 to 37 degrees C did not modify considerably the bound fractions. The same effects were observed as HSA concentration was modified. Binding assays of studied compounds to purified 1% (w/v) HSA at 0 degrees C, indicate that bound fraction of 2-7 ranges from 13 to 47%, exhibiting a higher affinity to HSA than AZT (12%), which would introduce some interesting improvements in their pharmacokinetic properties. In addition, by means of displacement studies using HSA site specific drugs such as diazepam and salicylate, it was determined that AZT binds to site I of the HSA molecule, by a mainly entropy driven process (DeltaS = 10.834 cal/mol degrees K), being these observations extensive to 2-7. Some structural basis to explain enhanced affinity of these novel derivatives was also established.

Simultaneous quantitation of intracellular zidovudine and lamivudine triphosphates in human immunodeficiency virus-infected individuals.

Highly active antiretroviral therapy (HAART) is the standard treatment for infection with human immunodeficiency virus (HIV). The most common HAART regimen consists of the combination of at least one protease inhibitor (PI) with two nucleoside reverse transcriptase inhibitors (NRTIs). Contrary to PIs, NRTIs require intracellular activation from the parent compound of their triphosphate moiety to suppress HIV replication. Simultaneous intracellular determination of two NRTI triphosphates is difficult to accomplish due to their relatively small concentrations in peripheral blood mononuclear cells (PBMCs), requiring large amounts of blood from HIV-positive patients. Recently, we described a method to determine intracellular zidovudine triphosphate (ZDV-TP) concentrations in HIV-infected patients by using solid-phase extraction and tandem mass spectrometry. The limit of quantitation (LOQ) for ZDV-TP was 0.10 pmol, and the method was successfully used for the determination of ZDV-TP in HIV-positive patients. In this study, we enhanced the aforementioned method by the simultaneous quantitation of ZDV-TP and lamivudine triphosphate (3TC-TP) in PBMCs from HIV-infected patients. The LOQ for 3TC-TP was 4.0 pmol, with an interassay coefficient of variation and an accuracy of 7 and 12%, respectively. This method was successfully applied to the simultaneous in vivo determination of the ZDV-TP and 3TC-TP pharmacokinetic profiles from HIV-infected patients receiving HAART.

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus.

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.