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Synthesis and evaluation of inhibitors of glycinamide ribonucleotide transformylase and fatty acid amide hydrolase
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ISBN 9781243979926
REGISTERED: 11/02/17
UPDATED: 11/21/17
Synthesis and evaluation of inhibitors of glycinamide ribonucleotide transformylase and fatty acid amide hydrolase.
Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors and has emerged as a productive target for antineoplastic therapeutic intervention. A comprehensive review of GAR Tfase as a target for cancer therapy is included. The synthesis and biological evaluation of nonpolyglutamatable inhibitors is reported. This work revealed a potent inhibitor of GAR Tfase that does not rely on


Specifications
  • ISBN bar code 9781243979926 ξ1 registered April 12 2016
  • Product category is Synthesis-and-evaluation-of-inhibitors-of-glycinamide-ribonucleotide-transformylase-and-fatty-acid-amide-hydrolase Jessica-K-DeMartino Book

Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors and has emerged as a productive target for antineoplastic therapeutic intervention. A comprehensive review of GAR Tfase as a target for cancer therapy is included. The synthesis and biological evaluation of nonpolyglutamatable inhibitors is reported. This work revealed a potent inhibitor of GAR Tfase that does not rely on polyglutamation for activity. Additionally, the asymmetric synthesis and evaluation of the two diastereomers of 10-methylthio-DDACTHF and related analogues as potential inhibitors of GAR Tfase are reported. This work, which defines the importance of the C10 stereochemistry for this class of inhibitors of GAR Tfase, revealed that both diastereomers are potent inhibitors of rhGAR Tfase (10R-3.3 K i = 210 nM, 10S-3.3 K i = 180 nM) that exhibit effective cell growth inhibition (CCRF-CEM IC50 = 80 and 50 nM, respectively). A series of C4 substituted alpha-ketooxazoles were examined as inhibitors of the serine hydrolase fatty acid amide hydrolase (FAAH) in efforts that further define and generalize a fundamental substituent effect on enzyme inhibitory potency. The synthesis of the series of inhibitors included a key halogen dance reaction to access the 4 position of the oxazole. A plot of the Hammett sigma m versus -log Ki provided a linear correlation (R2 = 0.90) with a slope of 3.37 (&rgr; = 3.37) that is of a magnitude that indicates the electron-withdrawing character of the substituent dominates its effects (a one sigmam unit change provides a >1000-fold change in K i).


References
    ^ Synthesis and evaluation of inhibitors of glycinamide ribonucleotide transformylase and fatty acid amide hydrolase. (revised Nov 2017)

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