Immucillins in custom catalytic-site cavities

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 22, 2008, Pages 5900-5903

  Murkin, Andrew S ^a   Clinch, Keith ^b   Mason, Jennifer M ^b   Tyler, Peter C ^b   Schramm, Vern L ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b CALLAGHAN INNOVATION   (New Zealand)

Author keywords

Binding; ImmH; Immucillin; Mutant; PNP; Transition state analogue

Indexed keywords

ENZYME INHIBITOR; FORODESINE; GLYCINE; HISTIDINE; MUTANT PROTEIN; PURINE NUCLEOSIDE PHOSPHORYLASE;

ARTICLE; CATALYSIS; DISSOCIATION CONSTANT; ENZYME ACTIVE SITE; ENZYME INHIBITION; ENZYME MECHANISM; HUMAN;

CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; GLYCINE; HISTIDINE; HUMANS; IMIDAZOLES; KINETICS; MUTATION; PROTEIN CONFORMATION; PURINE NUCLEOSIDES; PURINE-NUCLEOSIDE PHOSPHORYLASE; PYRIMIDINONES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 55249100481     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.08.047     Document Type: Article

References (15)

1. Abbreviations: PNP, purine nucleoside phosphorylase; ImmH, Immucillin-H; DADMe-ImmH, 4′-deaza-1′-aza-2′-deoxy-1′-(9-methylene)-ImmH; SerMe-ImmH, serinol-N-(9-methylene)-ImmH.
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7. ImmH (1) was synthesized as described in. Evans G.B., Furneaux R.H., Hutchison T.L., Kezar H.S., Morris Jr. P.E., Schramm V.L., and Tyler P.C. J. Org. Chem. 66 (2001) 5723
8. Murkin A.S., Birck M.R., Rinaldo-Matthis A., Shi W.X., Taylor E.A., Almo S.C., and Schramm V.L. Biochemistry 46 (2007) 5038
9. DADMe-ImmH (4) was synthesized as described in. Evans G.B., Furneaux R.H., Tyler P.C., and Schramm V.L. Org. Lett. 5 (2003) 3639
10. SerMe-ImmH (9) was prepared by reductive amination between serinol and 7-benzyloxymethyl-6-methoxy-9-carbaldehyde-9-deazahypoxanthine using sodium cyanoborohydride, followed by protecting-group removal with conc. HCl. Identity and purity were confirmed by NMR, ESI-MS, and elemental analysis. Full experimental details will be published elsewhere: Clinch, K.; Evans, G. B.; Furneaux, R. H.; Kelly, P. M.; Legentil, L.; Murkin, A. S.; Li, L.; Schramm, V. L.; Tyler, P. C.; Woolhouse, A. D., in preparation.
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14. +; Calcd 313.1135, found 313.1136. Dissolution in methanolic HCl and concentration to dryness gave the hydrochloride salt.
15. + Calcd 269.1072, found 269.1069.