Simplified analogues of immucillin-G retain potent human purine nucleoside phosphorylase inhibitory activity.

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Semeraro T, Lossani A, Botta M, Ghiron C, Alvarez R, Manetti F, Mugnaini C, Valensin S, Focher F, Corelli F

Simplified analogues of immucillin-G retain potent human purine nucleoside phosphorylase inhibitory activity.

J Med Chem. 2006 Oct 5;49(20):6037-45.

PubMed ID

17004717 [ View in PubMed

]

Abstract

A set of deazaguanine derivatives 1-3 targeting human purine nucleoside phosphorylase (hPNP) have been designed and synthesized. The new compounds are characterized by the presence of a structurally simplified "azasugar" motif to be more easily accessible by chemical synthesis than previous inhibitors. In the enzymatic assays, some of the new derivatives proved to be able to inhibit hPNP at low nanomolar concentration, thereby showing the same inhibitory potency in vitro as immucillin-H (IMH). Molecular docking experiments revealed a binding mode to hPNP essentially identical to that of IMH. As a result, the lower in vivo activity exhibited by 1d, compared with that exhibited by IMH, might be ascribed to differences in the pharmacokinetic, rather than pharmacodynamic, profile between these compounds. Derivatives 1a, 1d, and 2c emerged as the most active compounds within this new set and may represent interesting leads in the search for novel hPNP inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Forodesine	Purine nucleoside phosphorylase	IC 50 (nM)	3.5	N/A	N/A	Details
Forodesine	Purine nucleoside phosphorylase	Ki (nM)	1.8	N/A	N/A	Details