Application of difluoromethylene phosphonic acids to development of biologically active nucleotides

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1) 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 ω-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 nM and 8.1 nM vs 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 vs human enzyme, with an apparent inhibition constant of 53 nM (in the presence of 1mM phosphate).2) The bisphosphate derivatives of naturally occurring nucleosides including adenosine 3',5'-bisphosphate (A3P5P) are reported to act as competitive antagonists or partial agonists of P2Y1 receptors. A selective P2Y1 receptor antagonist is believed to have potential as an antithrombotic agent, while a selective receptor agonist may have potential as an antihypertensive or antidiabetic agent. Therefore, a variety of modified nucleotide analogues were synthesized to discuss the structure-activity relationships to P2Y1 receptor antagonists and agonists. Among them, MRS2179 is reported to show selective antagonist activities against P2Y1 receptor. However, the effect of MRS2179 on ex vivo platelet aggregation was strong but of short duration. To develop a phosphatase-resistant P2Y1 receptor antagonist, we examined to synthetic routes to modified nucleotide analogues for P2Y1 receptor ligands, in which one or two of phosphate groups for MRS2216 are replaced by a difluoromethylenephosphonyl group.