Multisubstrate analogue

A J. Broom, Rational Design of Enzyme Inhibitors Multisubstrate Analogue Inhibitors ,/ Med Chem. 1989, 32 2-7. 

Selected entries from Methods in Enzymology [vol, page(s)] Acetylthiocholine as substrate, 251, 101-102 assay by ESR, 251, 102-105 inhibitors, 251, 103 modification by symmetrical disulfide radical, 251, 100 thioester substrate, 248, 16 transition state and multisubstrate analogues, 249, 305 enzyme receptor, similarity to collagen, 245, 3. 

A short time later, these authors reported an elegant adaptation of this work for the synthesis of multisubstrate analogues (170a-c) of the proposed intermediate in the thymidylate synthase-mediated synthesis of thymidylic acid, as... 

Very recently, Broom and Yang have prepared new, flexible multisubstrate analogues (330) of (170) which retain all of the appropriate groups necessary for enzymatic binding but do not suffer from the problems associated with... 

Cyclic phosphonate analogues of PMEA (36) have been obtained after stereoselective cyclisation of an acyclic phosphonyl intermediate to the phos-phonyltetrahydrofuran nucleoside derivative. A series of cyclopropylphos-phonate analogues (37) has been synthesised stereoselectively via intramolecular epoxide opening reaction of y,5-epoxyalkanephosphonates with subsequent Mitsunobu coupling reaction to purine bases. Acyclic phosphonate derivatives of thymine (38-43) have been prepared and evaluated as multisubstrate analogue inhibitors of Escherichia coli thymidine phosphor-... 

Yokomatsu, T., Hayakawa, Y, Kihara, T., Koyanagi, S., Soeda, S., Shimeno, H., and Shibuya, S., Synthesis and evaluation of multisubstrate analogue inhibitors of purine nucleoside phosphorylases, Bioorg. Med. Chem., 8, 2571, 2000. 

A review on the rational design of enzyme inhibitors with particular regard to multisubstrate analogue inhibitors includes extensive discussion of examples drawn from the nucleotide field. The compounds (81) have been prepared by... 

In the preparation of the multisubstrate analogue (III.140) [39], diethyl 8-deazafolate (III.126) was reduced catalytically with Pt02 in ethanolic HCl to obtain a 60% yield of the tetrahydro derivative (III.141). Condensation of (III. 141) with 2 -0-acetyl-5 -[bis(2,2,2-triehloroethyl)phosphono]-5-bromo-methyl-2 -deoxyuridine in dry DMF in the presence of NaHCOj, followed by phosphate deprotection with Zn/Cu couple and acetylacetone, and finally ester hydrolysis, afforded a 41% overall yield (3 steps) of (III.140). 

TRANSITION-STATE ANALOGUE MULTISUBSTRATE MECHANISMS MUSCLE MASS DETERMINATION BY ISOTOPIC TRACERS MUTAROTASES ANOMERS... 

S Additional information <3, 7> (<3> enzyme exists in different conformational states with different substrate kinetic properties [9] <3> presumably one common nucleoside acceptor site [15] <3> purine deoxynucleo-side activity inseparably associated with deoxycytidine kinase protein [16] <3> several isozymes cytosolic deoxycytidine kinase I and II, plus mitochondrial isozyme [10] <3> multisubstrate enzyme, that also phos-phorylates purine deoxyribonucleotides [9] <7> enzyme has two separate active sites for deoxycytidine and deoxyadenosine activity [22] <3> reacts with both enantiomers of -deoxycytidine, -deoxyguanidine, -deoxyadenosine, and a-D-deoxycytidine is also substrate [31] <3> reacts with both enantiomers of jS-deoxyadenosine, j3-arabinofuranosyl-adenine and jd-deoxyguanine ]34] <3> remarkably relaxed enantioselectivity with respect to cytidine derivatives in p configuration [36] <3> lack of enantioselectivity for D- and L-analogues of cytidine and adenosine [43]) [9, 10, 15, 16, 22, 31, 34, 43]... 

Bisubstrate analogues are a variation on this approach. Covalent linkage of two of the substrates of a multisubstrate enzyme may lead to surprisingly potent inhibition, even exceeding what is expected on the basis of the enzyme s tinity for the two substrates individually. This approach requires that the two substrates are bound at the same time, i.e., a sequential rather than ping pong kinetic mechanism. 

Diab et al ° reported a series of fluorophosphonylated pyrimidine nucleosides (58). These analogues act as thymidine phosphorylase multisubstrate inhibitors. 

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