Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.
Basic Information
ID: ALA3108778
Journal: J Med Chem
Title: Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.
Authors: Vodnala SK, Lundbäck T, Yeheskieli E, Sjöberg B, Gustavsson AL, Svensson R, Olivera GC, Eze AA, de Koning HP, Hammarström LG, Rottenberg ME.
Abstract: Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, 1a) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro-3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics.
CiteXplore: 24283924
DOI: 10.1021/jm401530a
Patent ID: ┄