Synthesis and biological evaluation of 9-deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid as multi-substrate analogue inhibitors of PNP.

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Hikishima S, Hashimoto M, Magnowska L, Bzowska A, Yokomatsu T

Synthesis and biological evaluation of 9-deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid as multi-substrate analogue inhibitors of PNP.

Bioorg Med Chem Lett. 2007 Aug 1;17(15):4173-7. Epub 2007 May 21.

PubMed ID

17544667 [ View in PubMed

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Abstract

9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) was designed as a multi-substrate analogue inhibitor against purine nucleoside phosphorylase (PNP) on the basis of X-ray crystallographic data obtained for a binary complex of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine (DFPP-G) with calf spleen PNP. DFPP-DG and its analogous compounds were adjusted by length of the linker achieved by the Sonogashira-coupling reaction between a 9-deaza-9-iodoguanine derivative and omega-alkynyldifluoromethylene phosphonates as a key reaction. DFPP-DG is a very potent PNP inhibitor with apparent inhibition constants (in the presence of 1 mM phosphate) of 4.4 and 8.1 nM versus calf spleen and human erythrocyte PNPs, respectively. One of its analogues, homo-DFPP-DG, with longer chain linking phosphonate and 9-deazaguanine is even more potent versus human enzyme, with an apparent inhibition constant of 5.3 nM (in the presence of 1mM phosphate).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
9-(5,5-Difluoro-5-Phosphonopentyl)Guanine	Purine nucleoside phosphorylase	IC 50 (nM)	20.2	N/A	N/A	Details