ABSTRACT
Some 2',3'-dideoxynucleotides, of importance in the enzymology of the anti-HIV compounds, ddA and ddI, have been synthesized and purified by ion-exchange chromatography. 2',3'-Dideoxyadenylosuccinate, an intermediate in the pathway of ddI to ddATP, is converted to ddAMP by AMPS lyase at 1.85% of the efficiency of the natural substrate, adenylosuccinate. Interestingly, ddAMP and other 2',3'-dideoxygenated nucleotides are not substrates for AMP deaminase, another relevant enzyme in the conversion of ddA to ddATP via ddI.
Subject(s)
AMP Deaminase/metabolism , Adenylosuccinate Lyase/metabolism , Didanosine/metabolism , Dideoxyadenosine/metabolism , HIV/drug effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Deoxyadenine Nucleotides/biosynthesis , Deoxyadenine Nucleotides/metabolism , Didanosine/pharmacology , Dideoxyadenosine/pharmacology , Dideoxynucleotides , Succinates/metabolismABSTRACT
2',3'-Dideoxyadenosine (ddA) analogues with a variety of functionalization at the 2-position have been synthesized by a combination of thermal, photochemical and metal-mediated methodologies. These compounds are either totally resistant to deamination by mammalian adenosine deaminase (ADA) or are very poor substrates of ADA. They are competitive inhibitors of this enzyme.
