Phospho compounds, active

Another anti-herpes compound is the remarkably simple foscarnet (9.15, phospho-noformate). This is an inorganic pyrophosphate compound that inhibits viral DNA polymerase and RNA polymerase without requiring activation by phosphorylation. Fomivirsen is an oligonucleotide that inhibits human cytomegalovirus (CMV) via an... 

Like inorganic phosphate, inorganic sulfate can be converted into an activated form in which the sulfate resembles the terminal phospho group of ATP (Eq. 17-38). The resulting activated sulfo group can be transferred to other compounds including enzymes. Formation of... 

Several uncertainties have complicated our understanding of the role of Ca2+ in signaling. What is the source of Ca2+ How much of it enters cells from the outside and how much is released from internal stores Where are the internal stores What other kinds of ion channels are present and what second messengers regulate them The sarcoplasmic reticulum of skeletal muscle and also membranes in many other cells contain ryanodine receptors as well as InsP3 receptors.282 293 Both of these receptors have similar structures and contain Ca2+ channels. However, the ryanodine receptors are activated by cyclic ADP ribose (cADPR),294/295 which was first discovered as a compound inducing the release of Ca2+ in sea urchin eggs.296 The 2-phospho derivative of cADPR may also have a similar function.297... 

The enzyme was purified from Candida utilis in 1965 by Rosen et al. (8Q). Dried yeast was allowed to autolyze in phosphate buffer at pH 7.5 for 48 hr, and the enzyme was isolated in crystalline form from these autolysates by a procedure which included heating to 55° at pH 5.0, fractionation with ammonium sulfate, and purification on phospho-cellulose columns from which the enzyme was specifically eluted with malonate buffer containing 2.0 mM FDP. Crystallization was carried out by addition of ammonium sulfate in the presence of mM magnesium chloride. The Candida enzyme was more active than the mammalian FDPases at room temperature and pH 9.5 the crystalline protein catalyzed the hydrolysis of 83 /nnoles of FDP per minute per milligram of protein. The enzyme was completely inactive with other phosphate esters, including sedoheptulose diphosphate, ribulose diphosphate, and fructose 1- or fructose 6-phosphates. Nor was the activity of the enzyme inhibited by any of these compounds. Optimum activity was observed at concentrations of FDP between 0.05 and 0.5 mM higher concentrations of FDP (5 mM) were inhibitory. 

The UV-Vis data suggest that the subchromophores in 135 and 136 are near to being electronically independent. Derivative 135 has a small dipole moment and can be considered as an almost purely octupolar system, as is also the case for 136. Compared with their tin analogs, the phosphorus derivatives 135 and 136 have higher /3 values owing to the more efficient acceptor nature of the phospho-nium moiety [73 a]. Furthermore, the NLO activity of the octupolar compound 135 is almost three times larger than that of the dipolar subchromophore 137... 

Mechanism of action Cyclophosphamide [sye kloe FOSS fa mide] is the most commonly used alkylating agent. Both cyclophosphamide and ifosfamide [eye FOSS fa mide] are first biotransformed to hydroxylated intermediates by the cytochrome P-450 system (Figure 38.13). The hydroxylated intermediates undergo breakdown to form the active compounds, phospho-ramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. [Note The therapeutic effect of these drugs is independent of the level of activity of the cytochrome P-450 system.]... 

When the halogen compound employed in the first step has an activated halogen atom (RCH CHCHjX, QHjCHjX, XCH2CO2H) a simpler procedure known as the Horner phosphonate modification of the Wittig reaction is applicable. When benzyl chloride is heated with triethyl phosphite, ethyl chloride is eliminated from the initially formed phosphonium chloride with the production of diethyl benzylphosphonate. This phospho-... 

A uridine pyrophosphate derivative of Ai -acetyl-n-glucosamine which contains an extra phosphate group has been isolated from a hot-water extract of hen oviducts. Uridine 5-phosphate and uridine 5-pyrophosphate have been recovered from acid hydrolyzates of this compound. A diphosphate ester of A-acetyl-n-glucosamine can also be obtained from acid hydrolyzates of this uridine compound. Because of the catalytic activity of phospho-A -acetyl-n-glucosamine mutase toward it, it is probably AT-ace-tyl-D-glucosamine 1,6-diphosphate. 

Other synthetic compounds, such as polysulfates, phosphomannans, phospho-dextrans, thiazine derivatives, acridine derivatives, and the N,N-dioctadecyl-N, N,-bis(2 -hydroxyethyl) propanediamine will not be further discussed because their interferon-inducing activities have only been reported occasionally and have not been explored in sufficient detail. 

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

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