Shri Niwas

Synthesis Of 9-(1-Deoxy-1-phosphono-β-D-psicofuranosyl)-1,9-dihydro-6H-purin-6-one as a Potential Transition State Analog Inhibitor of Purine Nucleoside Phosphorylase

Abstract A fifteen-step synthesis of the proposed purine nucleoside phosphorylase (PNP) transition state analog inhibitor 9-(1-deoxy-1-phosphono-β-D-psicofuranosyl)-1,9-dihydro-6H-purine-6-one (2) is described starting with 1,2:4,5-disopropylidene-β-D-psicopyranose (12). Catalytic hydrogenation of 9-[3-O-benzyl-1-(dibenzyloxy-phosphinyl)-1-deoxy-β-D-psicofuranosyl]-6-benzyloxypurine (27b) under basic conditions gave the unstable 2 which was found to have a half-life of 39 min at pH 7 and 81 min at pH 8. The low PNP inhibitory activity found for 2 (IC50 = 25 μM at 50 mM phosphate concentration) may be due entirely to the presence of the decomposition product hypoxanthine which is itself an inhibitor (IC50 = 8.6 μM).

Inhibitors of purine nucleoside phosphorylase

Purine nucleoside phosphorylase (PNP) catalyzes reversible phosphorolysis of purine deoxy- and ribonucleosides with formation (d)Rib-1-P and corresponding bases. PNP plays a leading role in the cell metabolism of nucleosides and nucleotides, as well as in maintaining the immune status of an organism. The major aim of the majority of studies on the PNP is the detection of highly effective inhibitors of this enzyme, derivatives of purine nucleosides used in medicine as immunosuppressors, which are essential for creating selective T-cell immunodeficiency in a human body for organ and tissue transplantation. The present work is devoted to the study of the effects of some synthetic derivatives of purine nucleosides on activity of highly purified PNP from rabbit spleen and also from human healthy and tumor tissues of lung and kidneys. Purine nucleoside analogues modified at various positions of both the heterocyclic base and carbohydrate residues have been investigated. Several compounds, including 8-mercapto-acyclovir, 8-bromo-9-(3,4-hydroxybutyl)guanine, which demonstrated potent PNP inhibition, could be offered for subsequent study as immunosuppressors during organ and tissue transplantation.Disclosed is a compound containing a 2-amino-7-(R)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one wherein R is cyclohexenyl, cyclohexyl, or -CH2-R1, and wherein R1 is an optionally substituted heteroalicyclic, pyridinyl or alicyclic group. Also disclosed is a compound of formula (I), wherein R1 is H, NH?2?, or OCH3, R?2? is an optionally substituted cyclic group of 5-7 carbon atoms optionally containing one or more heteroatoms, R?3 and R4? are independently H or C?1?-4 alkyl, m is 0-4, n is 0-6, p is 0-1, X is CN, CSNH2, PO(OH)2, COOH, SO2NH2, NH2, OH CNHNH2, tetrazole, or triazole, COR?5? where R5 is C1-4 alkyl, CF3, NH2, or OC1-4 alkyl, and Y is O or NH.

Inhibition of the HER2 tyrosine kinase and characterization of a hydrophobic site near the nucleotide binding domain

Abstract A series of compounds was prepared to investigate the hydrophobic character of the HER2 receptor tyrosine kinase active site. These bisubstrate analogs contained hydrophobic moieties in place of the polar triphosphate and nucleoside fragments of the natural ATP ligand. Despite these modifications, good affinity was observed as measured by inhibition of receptor autophosphorylation.

Progress in the Synthesis of A Potential PNP Transition State Inhibitor

Abstract Phosphonic acid la has been proposed as a multisubstrate analog of the suggested transition state 1 for the PNP catalyzed reversible conversion of inosine and phosphate to hypoxanthine and ribose-1-phosphate. A 20 step synthesis of the monoethyl ester lb from D-fructose is described.