Carbonylbisphosphonate and (diazomethylene)bisphosphonate analogues of AZT 5′-diphosphate

A novel nucleotide analogue is described, in which the α,β-phosphoric anhydride oxygen of a nucleoside 5′-diphosphate is replaced by a carbonyl group: the carbonylbisphosphonate analogue 5 of 2′,3′-dideoxy-3′-azidothymidine 5′-diphosphate (AZT 5′-diphosphate). 5 was synthesized from tetramethyl (diazomethylene)bisphosphonate 1 via the trimethyl ester 4 of the corresponding AZT 5′-(diazomethylene)bisphosphonate 6, which is also a new type of nucleotide analogue. The ultimate product 5 was isolated by reverse-phase HPLC, and characterized by 31P, 13C, and 1H NMR; and by high-resolution mass spectrometry. The ketone group of 5 is a visible chromophore (yellow) and reversibly forms a colorless hydrate. The ketone hydrate ‘pK’ is about 4.2 when excess of magnesium ion is present. The potential of such analogues as novel inhibitors of enzymes mediating nucleotide-dependent biochemical processes is discussed.