Structure–activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis

Vodnala, S.K. et al. (2013) Structure–activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis. Journal of Medicinal Chemistry, 56(24), pp. 9861-9873. (doi:10.1021/jm401530a)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry
Authors: Vodnala, S.K., Lundbäck, T., Yeheskieli, E., Sjöberg, B., Gustavsson, A., Svensson, R., Olivera, G.C., Eze, A.A., De Koning, H.P., Hammarström, L.G.J., and Rottenberg, M.E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Medicinal Chemistry
ISSN:0022-2623
ISSN (Online):1520-4804

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