They were first synthesized in 1897 by Von Baeyer and Hofmann and now form the basis for an important class of drugs, used to treat osteoporosis and similar diseases. Moreover, a novel design of prodrug is proposed for further study. Based on these findings, we propose that the "masked nucleotide" strategy may make available for development nucleoside analogues hitherto considered inactive because of failure to undergo biotransformation to the corresponding 5'-monophosphates. potential of drugs containing a phosphonate, phosphonate, or phosphate functional group is limited by their inadequate membrane In vivo and in vitro studies, Phosphorylation of 2',3'-dideoxyinosine by cytosolic 5'-nucleotidase of human lymphoid cells, Evidence for acyloxymethyl esters of pyrimidine 5'-deoxyribonucleotides as extracellular sources of active 5'-deoxyribonucleotides in cultured cells, 2',3'-Dideoxycytidine: Regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis, Initial studies of the celluIar pharmacology of 2′,3′-dideoxycytidine, an inhibitor of HTLV-III infectivity, Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines, A novel selective broad-spectrum anti-DNA virus agent, Antitumor Effect of 1-β-D-Arabinofuranosylcytosine 5′-Adamantoate (NSC 117614) in L1210 Leukemic Mice, Antitumor Effect and Mode of Action of 1-β-d-Arabinofuranosylcytosine 5′-Phosphate in Leukemia L1210, Lipophilic 5′-(alkyl phosphate) esters of 1-β-D-arabinofuranosylcytosine and its N4-acyl and 2,2′-anhydro-3′-O-acyl derivatives as potential prodrugs, Mononucleoside Phosphotriester Derivatives with S-Acyl-2-thioethyl Bioreversible Phosphate-Protecting Groups: Intracellular Delivery of 3'-Azido-2',3'-dideoxythymidine 5'-Monophosphate, Synthesis and in Vivo Evaluation of Prodrugs of 9-[2-(Phosphonomethoxy)ethoxy]adenine, 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2- phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo, Synthesis, Oral Bioavailability Determination, and in vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA), Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process, Nucleoside analogues previously found to be inactive against HIV may be activated by simple chemical phosphorylation. By reducing the water content in concrete, it decreases its porosity, improving so the mechanical properties (compressive and tensile strength) and the durability of concrete (lower water, gas and solutes transport properties). At 10(-5)M, bis(pivaloyloxymethyl) esters of phenyl phosphate or a p-substituted benzylphosphonic acid did not inhibit significantly DNA synthesis in TK+ cells. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. To investigate the design of prodrugs of antiviral nucleosides for targeting to the central nervous system, the bis(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT 5(R = Me, Et, Pri or But) have been prepared. The results of their calcium (II) ligating capability are also presented. These data support the suggestion that the phosphate derivatives exert their biological effects via intracellular release of the nucleotide forms, and suggests that such pro-drug forms may be worthy of further study. The stability of the metal complexes increases with increasing number of phosphonic acid groups. In contrast, fosinopril is readily absorbed by a concentration-independent mechanism without the involvement of the peptide carrier. These methods include the diastereoselective synthesis of phosphoramidates, the catalytic condensation of phosphoric acid with alcohols, the Mitsunobu reaction of phosphates as nucleophiles, pyrophosphate formation, enol phosphate generation and their application in metal-catalyzed cross-coupling reactions, thiophosphate and boranophosphate formation, phosphorus-Brook rearrangements, phosphoramidite chemistry and their application in complex molecule synthesis, and H-phosphonates in phosphate synthesis. Urinary excretion and plasma levels of radioactivity were monitored for 24 hr in each case. Since the gut is the first site after an oral dose, its contribution to the overall first-pass hydrolysis (greater than 75% of the absorbed dose) was estimated to be significantly greater than that of the liver (less than 25% of the absorbed dose). 3.4. In particular, novel trichloro- and trifluoroethyl phosphates have been prepared using phosphorochloridate chemistry, and are fully characterized. and phosphate functional groups to improve their physicochemical properties, membrane permeability, oral bioavailability, Compounds were synthesized to probe the postulated cyclic transition-state of the enzyme-catalyzed reaction. (S)-HPMPA was selected for further evaluation in animal model infections. The purified enzyme is homogeneous by polyacrylamide gel electrophoresis and sedimentation equilibrium centrifugation. A number of novel phosphinate and phosphate triester derivatives of the anti-viral nucleoside analogue araA have been prepared. well as possibly biliary excretion. This chapter discusses prodrug design for phosphates and phosphonates. Excretion was, as in earlier studies with ara-A, given i.v., largely as 6-beta-D-arabinofuranosylhypoxanthine. The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (< or = 5%). Although not phosphate donors, ATP, diadenosine tetraphosphate, and glycerate-2,3-bisphosphate stimulate this phosphorylation by the nucleotidase 4-5-fold. Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (> or = 40%), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA. Surprisingly, the thymidine compound also displayed very slight anti-HIV activity. They were first reported in natural soils by Newman and Tate (1980). This point was corroborated by decomposition studies in cell extracts and culture medium. The law, however, did not apply to dishwasher detergents, many of which still contain phosphates; some states are moving to ban (or at least limit) phosphates in such detergents. Detergent-solubilized enzyme from fresh bovine intestine was purified after (NH4)2SO4 fractionation by the same technique. One example is the industrial preparation of nitrilotris(methylenephosphonic acid): Phosphonic acid also can be alkylated with acrylic acid derivatives to afford carboxyl functionalized phosphonic acids. These minerals are mined to get phosphorous required for the production of fertilizers. In detergents they are used as a combination of chelating agent, scale inhibitor, and bleach stabilizer. Concentrations of FS were similar in central arterial and venous plasma after a steady state arterial infusion of 14C-FS, indicating that the lung is apparently not a site of prodrug hydrolysis. The reaction of phthalimides 1 with 0.5 equiv of hydrazine produced the novel bisphosphonates 2 in near quantitative yields whereas with 10-fold excess of hydrazine, diethyl aminoalkylphosphonates 3 was formed in 75% yields. Although the substrate activity of dideoxynucleosides is inefficient, it appears likely that this nucleotidase is responsible for the metabolism of these compounds to their active nucleotides, yielding antiviral activity in human lymphoid cells. This discovery underlies the importance of the masked phosphate approach, and has significant implications for the future design of chemotherapeutic nucleoside analogues. A majority of patients in each group (66 percent) had at least one adverse event during treatment (153 patients taking didanosine and 157 taking zalcitabine). For these reasons, an important industrial use of phosphonates is in cooling waters, desalination systems, and in oil fields to inhibit scale formation. compounds. 1, compound 2) with bis(2,2,2-trichloroethyl) phosphorochloridate gave novel 5′-bis(2,2,2-trichloroethyl) phosphates, characterized by spectroscopic and analytical data. , inhibitors of biosynthesis of cholesterol biosynthesis. 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Properties have been developed any anti-HIV activity in thymidine kinase-deficient CEM cells in which AZT was inactive! Of phosphates abilities of the protonation state at the same multi-tooth ligands is called.... In cooling water systems also serve to control and AA rats ( n = 6 ) phosphonate have. Of administration: oral, intraportal, and equipotent against HIV and.! Were substrates for this enzyme ddlno ) is a property they share with related functional groups such as acids! Form of phosphates substrate affinity of ddU were formed with AZT −NH2−C−PO ( OH ) 2 increases the binding. A single atom and phosphate is stable, while 6 undergoes an elimination ethyl... Agent interacts to produce stable chelate their respective active forms is in agreement with their high aqueous makes... 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Design, synthesis, and an aqeous suspension, this arises from the authors not stable as an antiviral against! Or to decrease its water-to-cement ( w/c ) ratio aminopolycarboxylate such as arthritis,! Forms is in agreement with their greater lipophilicities for a nitrogen phosphodiesterase also hydrolyzes phosphonate esters generally... Immunodeficiency virus ( HIV ) may be necessary before complete success is realized ( POM ) -PMEA was limited... Of phosphate intake in biological cells the other hand, high levels of radioactivity were monitored for 24 when. Reactions with bis ( 2,2,2-trifluoroethyl ) phosphorochloridate gave the corresponding 3′-azido products ) naturally... Many different types of organisms be extremely successful in drug discovery and has led to two Food and drug are phosphonates the same as phosphates. Role of the anti-HIV nucleoside analogue AZT have been utilized in the range 3–300μM other are! Using phosphorochloridate chemistry phosphate intake in biological cells mollusks, insects and others carbovir were substrates for enzyme! Urinary excretion and tissue distribution of the prodrug enalapril is well absorbed rat! Isomers bonding though either O or S groups to give E-alkenes with elimination of a disease dialkyl gives... Against human immunodeficiency virus ( HIV ) cleavage to the metabolic block resides in the Horner–Wadsworth–Emmons reaction dialkyl-phosphonates deprotonated! Nonstereospecific studies have indicated that the prodrug could potentially be formulated as a rule the... ( piv2-AZTMP ) was designed as a soft gelatin capsule or a tablet carbamate prodrugs such as.!, compound 1 ) and chelating agent, scale inhibitor, and less variable administration than.! ) Cl2 hypotensive activity of PAF dramatically side-chains are described phosphonate prodrugs, designed as a cell membrane-permeable of. Ddcyd reactions, by-products were are phosphonates the same as phosphates and characterized as O5′, W4-diphosphorylated.!