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  • Title: Synthesis and biological evaluation of 9-deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid as multi-substrate analogue inhibitors of PNP.
    Author: Hikishima S, Hashimoto M, Magnowska L, Bzowska A, Yokomatsu T.
    Journal: Bioorg Med Chem Lett; 2007 Aug 01; 17(15):4173-7. PubMed ID: 17544667.
    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).
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