Sialyltransferases inhibitors

Finally, Schmidt and coworkers have similarly applied the hydroxylation of phosphonates for synthesis of some sialyltransferase inhibitors. Thus, the stabilized enolate of 71 was selectively oxidized using dichloro(camphorsulphonyl)oxaziridine (6) to produce the a-hydroxy diallylphosphonate in low yield but as a single stereoisomer. The reaction was also found to be effective for compounds containing a variety of ring substituents.59,60... 

ICgQ = 20 iM) were ako screened (Scheme 6.21) [46]. Similar azide-alkyne click coupling of azide-functionalized neuraminic acid with different nucleoside-based alkynes was extended for the creation of bacterial sialyltransferase inhibitor [47]. 

CMP, CDP, CTP, and synthetic derivatives of these nueleotides have been found to inhibit sialyltransferase activity.301" 02 Interest in such inhibitors is increasing, as they may be expected to serve as anticancer agents.269 901,303 Therefore, regulation of Golgi sialyltransferase activity appears possible by nucleotides as products of sialyl- and other glycosyl-transferase activities.1" 2 Interestingly, Epstein-Barr virus infection of human B, lymphoblastoid cell-lines leads to a diminution of sialyltransferase activity.304... 

Schmidt and co-workers have been investigating a series of potent inhibitors of a(2,6)-sialyl-transferase (O Fig. 9). They developed the transition analog 42 [153], based on the proposed mechanism of the sialyl transfer, that involves the partial dissociation of the CMP and the formation of the planer oxocarbenium ion structure in the transition state. They also found that the planer neuraminyl moiety in 42 can be replaced by the aromatic groups, leading to the readily accessible aromatic inhibitors of a(2,6)-sialyltransferase from rat liver. Further library... 

The cascade begins with stoichiometric amounts of phosphoenolpyruvate (PEP), 8-allyl-A-acetyl lactosamine 120, NeuAc 1, and catalytic quantities of ATP and CMP. Initially, CMP is converted to CDP by nucleoside monophosphate kinase (NMK) in the presence of ATP. The CDP produced reacts with PEP under pyruvate kinase (PK) catalysis to form CTP. Next, CMP-NeuAc synthetase catalyzes the in situ formation of the sialyl donor from NeuAc and CTP. The pyrophosphate byproduct is decomposed to inorganic phosphate by inorganic pyrophosphatase (PPase). Subsequently, the a-2,6-sialyltransferase accomplishes the sialyation of the lactosamine acceptor 120 and produces the ttansferase inhibitor CMP as a by-product. The CMP concentrations are kept low by conversion to CDP, and in so doing the problem of product inhibition is minimized. The cycle afforded 21% of the sialylated ttisac-charide 121, which is remarkable considering the complexity of the system and number of synthetic steps that can be avoided. 

Sialic acids as such, sialic acid derivatives, analogues, glycosides and sialo-oligosaccharides have been subject of many synthetic investigations. These studies were aimed at a further exploration of the properties of sialic acids, the preparation of substrates and inhibitors for sialidases, sialyltransferases or for sialic acid converting enzymes, and to make compounds accessable for analytical purposes or for studies related to metabolism or biological functions of sialic acids. 

The specific induction of de novo synthesis of sialyltransferase for glycolipid substrates by fatty acids has been studied in detail, and a hormonal regulation discussed by Fishman et al. (1976). Morphological changes in HeLa cells could be associated with the specific induction of LacCer sialyltransferase (IPNeu5AcLacCer formation), which was blocked by protein synthesis inhibitors. 

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