10.1016/j.bmc.2008.08.047
The research investigates the inhibition of ATP-mediated HIV-1 reverse transcriptase (RT) catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine (AZT) from AZT-terminated DNA primers by a series of 42 bisphosphonates. The purpose of the study was to identify potent bisphosphonate-based inhibitors with low cellular toxicity that could restore AZT sensitivity in HIV-1 strains that have developed resistance. The researchers found that the most active compounds had IC50 values <1 μM in excision inhibition assays and were halogen-substituted phenyl or biphenyl sidechains. They utilized quantitative structure–activity relationship (QSAR) methods, including comparative molecular similarity analysis, to develop a classification model with 94% accuracy and a regression model that closely matched experimental data. The study concluded that it might be possible to develop bisphosphonate-based AZT-excision inhibitors with minimal cellular toxicity, offering a new approach to combat resistant HIV-1 strains. The chemicals used in the process included various bisphosphonates, AZT, ATP, and other reagents for the synthesis and biological activity testing of the compounds.
10.1016/j.bmc.2011.08.069
The research aimed to develop novel phosphonate prodrugs of AZT with potential anticancer properties. The study synthesized a series of N-alkyl 5-chloromethylphosphonates of 3-azido-3-deoxythymidine (AZT) using P-chloromethylphosphonic ditriazolide as the phosphonylating agent. These compounds were evaluated for cytotoxic activity in two human cancer cell lines: oral (KB) and breast (MCF-7). The most active compound, phosphonamidate 8 with an N-n-propyl substituent, showed moderate cytotoxicity (IC50 values of 5.8 μg/mL in KB cells and 3.7 μg/mL in MCF-7 cells), though it was less potent than the parent AZT. Hydrolysis studies indicated that these phosphonamidates likely act as prodrugs of AZT, releasing the active nucleoside upon hydrolysis. Transport measurements using Caco-2 cell monolayers showed that the most active compounds (8 and 10) could permeate the intestinal epithelium, suggesting moderate oral bioavailability. The study concluded that these phosphonamidates could serve as promising prodrugs for AZT, potentially enhancing its anticancer activity and delivery.
10.1248/cpb.38.2597
The research focuses on the synthesis and evaluation of the anti-human Immunodeficiency Virus (HIV-1) activity of 3'-deoxy-3'-(triazol-1-yl)thymidines and 2',3'-dideoxy-3'-(triazol-1-yl)uridines, as well as the inhibition of reverse transcriptase by their 5'-triphosphates. The researchers hypothesized that the triazole nitrogen atoms could mimic the distorted azido group found in effective HIV inhibitors like AZT. They synthesized these compounds using cyclization of 5'-trityl derivatives of AZT and CS-87 with a-ketophosphorus ylides and acetylenic compounds, followed by deprotection of the 5'-trityl group. Key chemicals involved in the research include 3'-azido-3'-deoxythymidine (AZT), 3'-azido-2',3'-dideoxyuridine (CS-87), 1,2,3-triazole derivatives, and various reagents such as methyl propiolate and dimethyl acetylenedicarboxylate (DMAD). However, despite the successful synthesis of these compounds, no significant activity against HIV-1 was observed, and their 5'-triphosphates showed no appreciable inhibitory activity against reverse transcriptase enzymes from HIV-1 and Rauscher murine leukemia virus (RLV).
10.1021/jm00128a034
The first article details the synthesis and evaluation of several 2,5’-anhydro analogues of known antiviral compounds for their potential activity against HIV and Rauscher-Murine leukemia virus (R-MuLV). The study found that while the parent compounds like AZT were more active against HIV-1, the 2,5’-anhydro analogues demonstrated significant antiviral activity with reduced cytotoxicity. Notably, the 2,5’-anhydro derivative of AZT (compound 13) had a considerably lower cytotoxicity (TCID50 >100 μM) compared to AZT (TCID50 29 μM). The second article explores the quantitative structure-activity relationships (QSAR) of 68 5-(substituted benzyl)-2,4-diaminopyrimidines on dihydrofolate reductase (DHFR) from Lactobacillus casei and chicken liver. The study aims to design new trimethoprim-type antifolates with higher selectivity for bacterial DHFR. The QSAR analysis aligns well with stereographic models of the enzyme's active sites, and the findings are used to discuss the broader challenge of developing selective inhibitors for drug design.
10.1039/c39890000997
T. Sudhakar Rao and Colin B. Reese describe a new method for synthesizing 2,3'-anhydrothymidine (3), a key intermediate in the production of the antiretroviral drug 3'-azido-3'-deoxythymidine (AZT). The authors discovered that heating thymidine (2) with an excess of diphenyl sulphite in dimethylacetamide solution in the presence of a catalytic amount of 1-methylimidazole at 156°C for 45 minutes yields 2,3'-anhydrothymidine (3) in approximately 65% yield. This method is advantageous over previous procedures, such as the use of 2-chloro-1-diethylamino-1,1,2-trifluoroethane, due to the greater accessibility of diphenyl sulphite. The synthesized 2,3'-anhydrothymidine (3) can then be converted into AZT by reacting with lithium azide, achieving a 71% yield of AZT. This streamlined synthesis offers a more efficient route for the production of AZT, which is crucial for the treatment of AIDS patients.
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