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Conformationally locked carbocyclic nucleoside analogues.
Dejmek, Milan ; Hřebabecký, Hubert (advisor) ; Černý, Miloslav (referee) ; Moravcová, Jitka (referee)
Three novel series of conformationally locked carbocyclic nucleoside analogues based on the bridgehead substituted norbornane bicyclic skeleton were prepared - analogues with the pseudosugar locked in the North, East or South conformation. These compounds were synthesized as structurally related substances to a commercially successful antiviral drug abacavir, which is used in the therapy of HIV. One of the goals was the exploration of the dependence of antiviral activities of prepared compounds on the conformation of their pseudosugar part. The key intermediates in the syntheses of the North and South analogues, amine precursors suitable for nucleobase construction, were prepared in several steps from easily accessible 5-carboxymethyl norbornene. Introduction of a carboxylic function into the bridgehead position, a key transformation mutual to both syntheses, was accomplished via the Hell-Volhard-Zelinsky bromination of norbornane-2- carboxylic acid, which affords rearranged 2-exo-bromo-1-carboxynorbornane. Approach to the derivatives locked in the East conformation is based on radical cyclization of substituted 4-(bromomethyl)cyclohexanone oxime, which affords norbornane intermediate substituted in both bridgehead positions. Thymine, 6-chloropurine and 2-amino-6-chloropurine nucleobases were used...
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