Novel and Convenient Approach to Synthesis of AZT/d4T H‐phosphonates

Abstract

Intensive efforts have been made to develop effective chemotherapeutic agents against the human immunodeficiency virus (HIV).' Nucleoside analogues are widely used as antiviral agents in ,the treatments of AIDS and the AIDS related complex? Currently, among the diversity of compounds, 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxy-2',3'-dehydrothymidine (d4T) were most extensively studied.' However, it has been proved that they must be phosphorylated intracellularly to their active txiphosphates before acting as competitive inhibitors or alternate substrates (chain terminators) of HIV RT.4 Furthermore, some clinical drawbacks such as the toxicity of AZT are subject to diurnal effects which may be related to monophosphorylation? Consequently, in order to overcome the decreased intracellular phosphorylation, a number of methods have been developed for the delivery of monophosphorylated antiviral nucleoside.6In various prodrugs, 5'-H-phosphonates of AZT and d4T as potent antiviral agents have shown promising, since in some cases they have exhibited enhanced antiviral activity and reduced cytotoxicity compared to the parent nucleosides. For example, 5'-H-phosphonate of AZT (Scheme 1, l), which is in Phase I clinical trials currently, is much less toxic than AZT, CCm values of 1 and AZT are 2.5 mmol L-' and 210 pmol L-' respectively? Selective indexes of AZT S-cyclohexylphosphite (Scheme 1 . 2~) and d4T 5'-isopropylphosphite (Scheme 1, 2b) are 18.9 and more than 6.11 times respectively compared with AZT and d4T.* H-phosphonate monoesters were usually synthesized through the reaction of alcohols with phosphorus trichloriddmazole and the following hydrolysis in ' triethylammonium bicarbonate aqueous solution9 or the mono-substitution of diphenyl phosphite by alcohols and the subsequent hydrolysis in triethylamindwater. ** H-phosphonate diesters are prepared by condensation of H-phosphonate monoesters with alcohols in the presence of condensing agents" or hydrolysis of hos phoramidates in the presence of IH-tetrazole." Buj these methods suffered from laborious synthetic procedure, variable yields, and incompatibility with the common protecting groups utilized in natural product chemistry. Therefore, we try to develop a convenient, efficient, and general method for the preparation of H-phosphonate mono and diesters.scheme 1 2'bIn this paper, mono and diesters of H-phosphonates were synthesized through reaction of phosphonic acid with different alcohols in the presence of pivaloyl chloride (PV-Cl). As shown in Scheme 2, the general procedure was as follows: At mom temperature, 1.1 equiv. of PV-Cl was added dropwise to the mixture of AZT or *

Electrokinetic Phenomena of Sulfonated-Polyethersulfone Ultrafiltration Membrane Modified by TiO₂ Nanoparticles

“…Figure 3 also clearly shows a shift of the IEPs towards a lower pH value for the SPES membrane modified by nano-TiO 2 . The isoelectric points of the TiO 2 modified membrane is located at about 2.9, which is less than the IEPs of TiO 2 nanoparticles (pH at about 4.3) [11]. Thus, this membrane reveals a more acid characteristic than the unmodified membrane.…”

Synthesis, Characterization and Docking Study of Novel Pyrimidine Derivatives as Anticancer Agents

“…Gene-therapy in recent research was based on DNA and its modification [8][9][10]. The thymidine ring is a DNA building block that interests many researchers to focused their research on the synthesis of new pyrimidine rings as anti-cancer agents such as 5-fluorouracil [1][2][3][4][5][6][7][8][9][10][11][12][13][14], and anti-HIV like AZT, D4T, Nikavir [15][16][17][18][19][20][21], Lamivudina [22] and Emtricitabina [16,[23][24]. The Nitrogen containing heterocycles like pyrimidines and their derivatives have received great attention for their considerable exciting biological activities [25][26][27][28].…”

Stereochemical Investigation of a Novel Biological Active Substance from the Secondary Metabolites of Marine Fungus Penicillium chrysogenum SYP-F-2720

“…As the most primitive multicultural marine fungus organisms, sponge is an important source of natural active ingredients [7,8]. To data, numerous novel biological active substance with antitumor, antiviral, antibacterial, anti-inflammatory, and enzyme inhibitory activities have been isolated from sponge-derived marine fungus, such as aspergione A-F from Aspergillus versicolor, evariquinone and isoemericellin from Emericella variecolor, isocyclocitrinol A from Penicillium citrinum, sorbicillactones A from Penicillium chrysogenum [7][8][9][10][11][12]. SYP-F-2720 is a sponge-derived marine fungus belongs to P. chrysogenum strain, which is no relevant research on it so far.…”