The synthesis and metal binding characteristics of novel, isopolar phosphonate analogues of nucleotides

Abstract

Dichloromethylene-, difluoromethylene-, and fluoromethylene-bisphosphonic acids condense with the 5′-phosphoromorpholidates of adenosine and guanosine to give nucleotide analogues of ATP and GTP which are isopolar and isosteric. An isopolar but non-isosteric analogue of ATP results from the condensation of acetylene-1,2-bisphosphonic acid with AMP-morpholidate.

³¹ P N.m.r. and pK_a, data show that the physical analogy improves in the series CH₂ < CCl₂⩽ CFH < CF₂ < CC < O with respect to the β,γ-bridging function. N.m.r. and ion-selective electrode measurements on the binding of the divalent metals Mg, Ca, Zn, and Ba suggest that the pattern of metal cation binding to the nucleotide tetra-anion responds both to steric and to electronic features of the phosphonates, with the β,γ-difluoromethylene analogue most closely resembling ATP.