Sodium phosphorothioate

Sodium phosphoramidate, Na2P03NH2, 6 100, 101 Sodium phosphorothioate, Na3-P03S, 6 102 12-hydrate, 5 103 Sodium pyrophosphates, 3 98 Na2H2P2C>7, 3 99 Na4P2C>7, 3 100 Sodium pyrosullite, 2 162, 164 and its 7-hydrate, 2 165 Sodium rare earth sulfates, 2 42, 46... 

To circumvent this problem it was found advantageous to use a slight excess of sodium hydroxide in the reaction, i.e., a 5% excess of the required 6 molar equivalents. This ensures that the solution is basic enough to prevent decomposition of the sodium phosphorothioate once it is formed. Yasuda and Lambert reported a percentage yield of 57% of the theoretical. In a series of three preparations on roughly a 1-mol scale where 5% excess base was used, we obtained an average yield of 67%. It was also possible to scale down the reaction to permit synthesis of 35S-labeled sodium phosphorothioate. In a series of four syntheses on a 4-5-millimol scale an average yield of 59% was achieved. 

Methods of preparing O-S esters are numerous and very varied (9.396-9.402). They include heating an alkyl halide with sodium phosphorothioate (9.396) or a diester (9.397), and heating a trialkyl phosphite with sulphenyl chloride (9.398). 

Symmetrical thiohypophosphate esters can be made from sodium phosphorothioates and chloro-phosphonothionates (9.535). These esters usually hydrolyse easily as (9.536), but stme cycUc derivatives such as (9.537) (X, Y = 0, S, Se) are very resistant. These latter compounds are colourless, water-insoluble crystalline solids with high melting points. 

Sodium phosphorothioate added portionwise during 15 min. below 35° to a stirred soln. of 3-bromo-2-(bromomethyl) propionic acid in aq. NaHC03, stirring continued 5 hrs. at 25-30°, refrigerated overnight, purged with Ng, coned. HCl added, and heated 10 min. at 90-95° 3-mercapto-2-(mercaptomethyl) pro-... 

Methyl parathion is an organophosphorus insecticide that is commercially produced in the United States and abroad. Methyl parathion, 0,0-dimethyl 0-(4-nitrophenyl) phosphorothioate, is not known to occur as a natural substance (lARC 1983). It is commercially produced by the reaction of 0,0-dimethyl phos-phorochloridothionate and the sodium salt of 4-nitrophenol in acetone solvent (EPA 1974b HSDB 1999 NIOSH 1976 NRC 1977 Worthing 1979). 

A new antiviral agent, developed for treatment of CMV retinitis, can be administered by intravitreal injection. Formivirsen sodium is a phosphorothioate oligonucleotide that inhibits CMV replication through an antisense mechanism. It is formulated as a sterile and preservative-free solution and supplied in single-use vials (Vitravene ). The product is administered directly into the vitreous cavity posterior to the limbus through a 30-gauge needle. This procedure can be performed on an... 

Oberbauer et al. reported inhibition of a sodium/phosphate (Na/Pi-2) co-transporter by phosphorothioated AS-ODN. A single intravenous injection of the AS-ODN inhibited both the mRNA and the protein for the Na/Pi-2 co-transporter, and conseqnently snppressed In-minal uptake of phosphate by the proximal tubules [130],... 

Wang et al. injected a Texas-red-labelled phosphorothioated AS-ODN into the dopamine lA receptor in the rat renal interstitium. Fluorescence was detected after 24 h in both tubular epithelium and intra-renal vasculature. Treatment resulted in a 35% decrease in the dopamine lA receptor protein, causing a reduction in urinary sodium excretion and urine output [131],... 

Previous studies have reported that ERKs are characteristically associated with cell proliferation and protection from apoptosis (Bl, XI), while activation of JNK and p38 MAPK can promote apoptosis in many systems, including B lymphocytes (G5), cerebellar granule cells (K3), hematopoietic cells (K8), and neuronal cells (M3, XI). On the other hand, a recent report found that a pyridinyl imidazole, SB 202190, the specific inhibitor of p38 MAPK, by itself was sufficient to induce apoptosis in T lymphocyte Jurkat cells (N2). Moreover, Th-2-derived cytokine IL-5, the ERK activator and antiapoptotic factor for eosinophils, could also activate p38 MAPK in human eosinophils (BIO). We recently reported that cytokine IL-3, IL-5, and GM-CSF could prolong survival of human eosinophilic leukemic (EoL-1) cells through the transient activation of ERK (W15). On the other hand, activation of p38 MAPK in EoL-1 cells by the NSAID sodium salicylate (NaSal) could lead to apoptosis (W15). We also found that the suppression of ERK using ERK antisense phosphorothioate oligodeoxynucleotides could promote the apoptosis of peripheral blood eosinophils (W16). Moreover, we found that dexamethasone-induced apoptosis and activation of JNK and p38 MAPK activity in eosinophils are regulated by caspases (Z2). 

A. General description Fomivirsen sodium (molecular weight about 7kDa) is a phosphorothioate oligonucleotide, 21 nucleotides in length, with the following sequence 5 -GCG TTT GCT CTT CTT CTT GCG-3. ... 

Di-(2-Ethylhexyl)Acid Phosphate Di-(2 Ethylhexyl)Adipate Di-(2-Ethylhexyl)Phosphate Di-(2-Ediylhexyl)Phosphoric Acid Di(2-Ethylhexyl) Phthalate Di-(2-Ethylhexyl)Sulfosuccinate Sodium Salt 0,0-Diethyl 0-(2-Isopropyl-6-Methyl -4-Pyrimidinyl)Phosphorothioate 0,0-Diethyl-0-(2-Isopropyl-6-Methyl-4-Pyrimidinyl) Phosphorothioate... 

The activity of sulfur towards platinum complexes has led to investigation of so-called rescue agents to ameliorate the side effects of platinum therapy, without compromising its anti-tumor activity. These nucleophilic sulfur compounds include sodium thiosulfate (STS), sodium diethyldithio-carbamate (Naddtc), (S)- 2-[(3-aminopropyl)amino]ethyl phosphorothioic acid (WR-2721, Ethyol , amifostine), glutathione (GSH), methionine, thiourea, cysteine, -acetylcysteine, penicillamine, biotin, sulfathiazole, sodium 2-mercaptoethanesulfonate (mesna), and its dimer (di)mesna (BNP-7787). The protective effect of these compounds is either due to prevention, or reversal of Pt-S adducts in proteins. Some of the more promising of the above-mentioned compounds (see Fig. 1) will be discussed below. 

The metabolic and/or hydrolytic products of parathion encountered as residues in the urine include both diethyl phosphoric acid and diethyl phosphorothioic acid, most probably as their salts (potassium or sodium). Derivatization of these residues with diazomethane would result in the formation of three trialkyl phosphate compounds, namely, 0,0-diethyl O-methyl phosphate (DEMMP), 0,0-diethyl 0-methyl phosphoro-thionate (DEMMTP), and 0,0-diethyl S-methyl phosphorothiolate (DEMMPTh). Earlier (15), it had been shown by combined gas chromatography-mass spectrometry and other analytical data that a later-eluting major product ca. 85%) of the methylation of diethyl phosphorothioic acid formed under the conditions of the analytical method was DEMMPTh, and the minor product formed (ca. 15%) was DEMMTP. Accordingly, all three trialkyl phosphates were observed and confirmed by mass spectrometry in the analysis of the human urine extract. Sufficient internal bond energy differences are associated with the isomeric structures DEMMPTh and DEMMTP that qualitatively and quantitatively dissimilar fragmentation patterns are observed for both isomers as can be seen from the mass spectra of these compounds shown in Figure 4. 

Vitravene (fomivirsen sodium, ISIS Pharmaceuticals see Table 9) remains the only antisense-based biopharmaceutical approved for general medical use (see also Part III, Chapter 3). The product is a 21-base phosphorothioate nucleotide that displays a base sequence complementary to certain human cytomegaloviral mRNA transcripts. Its administration inhibits viral replication through an antisense mechanism. Approved in the US in 1998 and in the EU in 1999, the product is indicated for the treatment of cytomegalovirus retinitis by intraocular injection in AIDS patients. It was withdrawn from the EU market in May 2002 for commercial reasons. 

Demeton-S (56) can also be prepared directly by the reaction of sodium 0,0-diethyl phosphorothioate with ethyl-2-chioroethyl sulfide or by the reaction of diethyl phosphorochloridate with sodium 2-ethylthioethyl mercaptide (Schrader, 1950a 1950b). 

The most important of the phosphorothiolic acid derivatives within this group is 0,0-dimethyl-S-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl] phosphorothioate (endothion, 77) prepared by Metivier (1955a 1955b) by the reaction of 2-chloromethyl-5-methoxy-4-oxo-4H-pyran with the sodium salt of 0,0-dimethyl phosphorothioate ... 

Anionic Sodium bis(2-ethylhexyl sulfosuccinate) [AOT] Bicyclic sulfonates Di(2-ethylhexyl) phosphoric acid [DEHPA] Di(2-ethylhexyl) phosphorothioic acid [DEPTA] Di(oleyl) phosphoric acid [DOLPA] Di(tridecyl) phosphoric acid Sodium dodecylbenzenesulfonate [SDBS]/1-butanol [4, and references therein] [5] [6,7] [8] [9,10] [11] [12]... 

Radioactive [35S]-phosphorothioates have been used for in vivo evaluation of chronic or cumulative toxicity of oligonucleotides. To achieve site-specific 35S-labeling in phosphoramidite chemistry, either a mixture of [35S]/carbon disulfide/pyridine/triethylamine [329] or 35S-la-beled Beaucage reagent [330] have been used in the sulfurization step. 3H- and 14C-labeled compounds have been tools in investigations of the metabolic fate of the nucleobases of an oligomer [331]. 3H may be inserted at the 5 -end by formation of the 5 -carboxyaldehyde by Mofatt-Pfitzner reagent, followed by reduction with [3H]-sodium borohydride in 2-propanol... 

The alkylation, with the more reactive of alkyl halides, of the sodium salts of monoes-terified phosphonothioic acids (equation 22) (see also Scheme 11) or of the disodium salts 107 results in preferential S-alkylation, and the same situation obtains for the salts of phosphinothioic acid " methylation can also be carried out with dimethyl sulphate. Alkylations may also be performed under phase-transfer conditions. From both practical and theoretical perspectives, the subject is more complex, since the course of alkylation reactions depends on the nature of the alkylating agent, on the polarity of solvent and whether this is protic or non-protic and on the concentrations of reactants a study of these features has been the subject of two reports In non-polar or weakly polar aprotic media, or in EtOH, alkylation occurs almost exclusively on sulphur, but in dipolar aprotic solvents, O-alkylation also takes place. The relative yields of sulphur- and oxygen-substituted derivatives, [Qs/Qol depends, for a given solvent, on the nature of substituents on phosphorus, i.e. essentially, whether the substrate is a thiophosphoric, thiophosphonic or thiophosphinic acid. With alkyl tosylates as alkylating agents at 0.02 m in hmpt, the alkylation of sodium 0,0-dialkyl or diphenyl phosphorothioates results in 100% overall conversions with [Qs/Qo] 5 the overall yields for sodium diphenyl- or diisopropyl-phosphinothioates are lower (50-100%) with [Qs/Qo] 1 ... 

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