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, 51 (18), 5880-4

A Beta-Fluoroamine Inhibitor of Purine Nucleoside Phosphorylase

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A Beta-Fluoroamine Inhibitor of Purine Nucleoside Phosphorylase

Jennifer M Mason et al. J Med Chem.

Abstract

The potent immucillin purine nucleoside phosphorylase (PNP ) inhibitors F-DADMe-ImmH [(3S,4S)-3], and [(3R,4R)-3] are synthesized in seven steps. Cycloaddition to a fluoroalkene and an enzymic resolution are the key features of the construction of the fluoropyrrolidines 11, from which the immucillins are assembled by use of a three-component Mannich reaction. Slow-onset binding constants (Ki(*)) for [(3S,4S)-3] and [(3R,4R)-3] with human PNP are 0.032 and 1.82 nM, respectively. F-DADMe-ImmH [(3S,4S)-3] exhibits oral availability in mice at doses as low as 0.2 mg/kg.

Figures

Figure 1
Figure 1
Structures of some immucillins and a precursor amine.
Figure 2
Figure 2
ORTEP(40) drawing of (3R,4R)−10.
Figure 3
Figure 3
Bioavailability of F-DADMe-ImmH in mice. Enzyme activity was assayed following administration of 14 nmol by oral treatment (■) or intraperitoneal injection (◆).
Scheme 1
Scheme 1
Synthesis of the Racemate and Enantiomers of F-DADMe-ImmH [(±)−3, (3S,4S)−3, and (3R,4R)−3]a a Reagents (a) TFA, CH2Cl2, 0°C, 64% from 7; (b) LiBH4, MeOH, Et2O, 0 °C then HCl, 50 °C, 80%; (c) H2, Pd−C, (Boc)2O, MeOH, 100%; (d) HCl, then 9-deazahypoxanthine, CH2O, NaOAc, water-dioxane, 100 °C, 40%; (e) NaOEt, EtOH, rt, 55%; (f) CAL-B, vinyl acetate, tert-BuOMe, 50 °C, 31% [(3S,4R)−8] and 30% [(3R,4S)−9].

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