Carbonylbisphosphonate and (diazomethylene)bisphosphonate analogues of AZT 5(')-diphosphate.
A novel nucleotide analogue is described, in which the alpha,beta-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.
McKenna
Charles E
CE
Department of Chemistry, College of Letters, Arts and Sciences, University of Southern California, University Park Campus, Los Angeles, CA 90089-0744, USA. mckenna@usc.edu
Kashemirov
Boris A
BA
Rozé
Christian N
CN
D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013053:Spectrophotometry; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification
D007202:Indicators and Reagents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine