Phosphorylation synthetic

Bn groups and Cbz protection, under which condition the amino Boc protection is stable. GPI 74 is the first fully phosphorylated synthetic GPI that was feasible for future coupling with peptides or proteins. 

A Acetylation, O-Phosphorylation, and O-Adenylylation. A/-Acetylation, O-phosphorjiation, and O-adenyljiation provide mechanisms by which therapeutically valuable aminocyclitol antibiotics, eg, kanamycia [8063-07-8] gentamicin [1403-66-3] sisomicin [32385-11-8], streptomycia [57-92-1], neomycin, or spectinomycin are rendered either partially or completely iaactive. Thus, eg, kanamycia B [4696-78-8] (50) can be iaactivated by modification at several sites, as shown. The elucidation of these mechanisms has allowed chemical modification of the sites at which the iaactivation occurs. Several such bioactive analogues, eg, dibekacia and amikacin have been prepared and are not subject to the iaactivation hence, they inhibit those organisms against which the parent antibiotics are iaeffective (96) (see Antibacterial agents, synthetic). 

The importance of quinones with unsaturated side chains in respiratory, photosynthetic, blood-clotting, and oxidative phosphorylation processes has stimulated much research in synthetic methods. The important alkyl- or polyisoprenyltin reagents, eg, (71) or (72), illustrate significant conversions of 2,3-dimethoxy-5-methyl-l,4-ben2oquinone [605-94-7] (73) to 75% (74) [727-81-1] and 94% (75) [4370-61-0] (71—73). 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

From this observation of the inhibition by adenosine, and other observations, Newell and Tucker suspected the existence of a common synthetic pathway for adenosine and thiamine, and proved (with the help of a collection of mutants) that the bifurcation occurred after the 5-amino- l-(P-D-ribofura-nosyl)imidazole 5 -phosphate (46) step (Scheme 23). Finally, they found that 5-amino-l-(0-D-ribofuranosyl)imidazole (47), labeled with l4C in the imidazole ring, was incorporated into pyramine without significant loss of molar radioactivity by a mutant that is able to use this nucleoside (presumably after phosphorylation).53,54... 

Functionally related to FruA is the novel class I fructose 6-phosphate aldolase (FSA) from E. coli, which catalyzes the reversible cleavage of fructose 6-phosphate (30) to give dihydroxyacetone (31) and d-(18) [90]. It is the only known enzyme that does not require the expensive phosphorylated nucleophile DHAP for synthetic purpose. 

A new synthetic route to 2-alkyl-4-aryl-l(2ff)-isoquinolones 77 involves the base promoted cyclization of phosphorylated o-aroylbenzamides <96T(52)4433>. 

Figure 5-8. Domain structure. Protein kinases contain two domains. The upper, amino terminal domain binds the phosphoryl donor ATP (light blue). The lower, carboxyl terminal domain is shown binding a synthetic peptide substrate (dark blue).

Synthetic nonhydrolyzable analogs of nucleoside triphosphates (Figure 33-13) allow investigators to distinguish the effects of nucleotides due to phosphoryl transfer from effects mediated by occupancy of allosteric nucleotide-binding sites on regulated enzymes. 

A. Synthetic Methods.—There have been no strikingly new approaches to the general problem of phosphorylation, but several ingenious methods of preparing suitable active esters under mild conditions have been reported. Typical of these is the reactive intermediate (1) formed from reaction of a mono- or di-ester of phosphoric acid with (2), itself produced by reaction of triphenylphosphine with bis(2-pyridyl) disulphide (preferably in the presence of mercuric ion as scavenger for the 2-mercaptopyridine liberated). 

The reaction of dipyridyl disulphide with triphenylphosphine to give the stable phosphonium salt (51) has been used in new methods of phosphorylation (reaction A), in peptide synthesis (reaction B), and in the formation of active esters of cx-amino-acids (reaction C). These reactions appear to have synthetic potential. 

The strategies used in the synthesis of polymethine dyes are illustrated for a series of indoline derivatives in Scheme 6.1. There is an even wider range of synthetic routes to polymethine dyes than is described here, but they are based for the most part on a similar set of principles. The starting material for the synthesis of this group of polymethine dyes is invariably 2-methylene-1,3,3-trimethylindolenine (121), known universally as Fischer s base. As illustrated in the scheme, compound 121 may be converted by formylation using phosphoryl chloride and dimethylformamide into compound 122, referred to as Fischer s aldehyde, which is also a useful starting material for this series of polymethine dyes. When compound 121 (2 mol) is heated with triethylorthoformate (1 mol) in the presence of a base such as pyridine, the symmetrical cyanine dye, C. I. Basic Red 12 109 is formed. The synthesis of some hemicyanines may be achieved by... 

The second chapter Synthesis and Biological Activity of 2,5-Dihydro-1,2-Oxaphosphole-2-Oxide Derivatives deals with the recent synthetic methods, particularly those using phosphorylated allenes as the starting materials, of these compounds which show interesting biological properties. 

Since thiophenes are regarded as being good substructures for organic electronic materials, phosphorylthiophenes are taken as reference compounds for thiophene based materials [45] and phosphorylthiophenes such as 16 are employed as synthetic intermediates for phosphoryl substituted organic electronic materials such as oligothiophenes or thienylene bridged donors (Scheme 26) [46],... 

All the synthetic protocols described above have limitations to some extent and the yields of the products were modest. In some cases the formation of 1,2-alkadi-enephosphonate derivatives is essential for obtaining the final cyclic products. This is the reason why many authors have used the higher reactivity of 1,2-alkadi-enephosphonates, discovered by Mark [42] in 1962 for the preparation of 2,5-dihydro-l,2-oxaphosphole-2-oxide derivatives. Since then, the oxaphospholic cyclization of 1,2-alkadienephosphonate system of double bonds has become the easiest method for the synthesis of these compounds. The special structure of phosphorylated allenes is responsible for their special properties, which has attracted the attention of chemists for a long time [43 16],... 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

An application of this synthetic strategy by the same group led to the development of a series of potent and selective allosteric Akt (protein kinase B/PKB) kinase inhibitors that induced apoptosis in tumor cells and inhibited Akt phosphorylation in vivo (Scheme 6.261) [451]. 

Arakawa, R., Hayashi, M., Remaley, A. T., Brewer, B. H., Yamauchi, Y. and Yokoyama, S. Phosphorylation and stabilization of ATP binding cassette transporter Al by synthetic amphiphilic helical peptides. /. Biol. Chem. 279 6217-6220,... 

The plasma membrane Ca2+-ATPase pump effects outward transport of Ca2+ against a large electrochemical gradient for Ca2+. The mechanism of the pump involves its phosphorylation by ATP and the formation of a high-energy intermediate. This basic mechanism is similar for both the plasma membrane and ER pumps however, the structures of these distinct gene products are substantially different. As discussed below, the ER pump, sometimes called a sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) pump, is inhibited potently by certain natural and synthetic toxins that do not affect the plasma membrane pump. The plasma membrane pump, but not the SERCA pump, is controlled in part by Ca2+ calmodulin, allowing for rapid activation when cytoplasmic Ca2+ rises. 

Wadsworth, W.S., Synthetic applications of phosphoryl-stabilized anions, Org. React., 25, 73, 1977. 

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