| Abstrakt: |
Moffatt oxidation of 2,3-O-isopropylideneuridine (1a) and treatment of the crude 5-aldehyde with formylmethylene-stabilized Wittig reagent gave the vinylogously extended 7-aldehyde 2a. Condensation of 2a with ethoxycarbonyl- or dibromomethylene phosphorane reagents gave the conjugated dienes 6a and 4a, respectively. Deacetonization gave diene ester 7a [5(E),7(E); with s-trans conformation] and dibromodiene 5a [5(E)], respectively. Analogously, 2,3-O-isopropylideneadenosine (1b) was Wittig-extended into the conjugated dibromodiene 5b [5(E)] and dienoic ester 7b [5(E),7(E)]. Furthermore, palladium-catalyzed coupling of the vinyl 6(E)-stannanes 14 with (E) and (Z) ethyl 3-iodoacrylate gave stereodefined access to dienoic esters 7 (E,E) and 16 (E,Z). Incubation of AdoHcy hydrolase with 100 μM of 5b resulted in partial inhibition of the enzyme without any apparent change in the enzyme's nicotinamide adenine dinucleoside (NAD+) content. In contrast, 7b and 16b produced time- and concentration-dependent inactivation of S-adenosyl-l-homocysteine (AdoHcy) hydrolase producing significant decreases in the enzyme's NAD+ content. However, 7b and 16b upon incubation with AdoHcy hydrolase were not metabolized suggesting that these compounds are type I mechanism-based inhibitors. No specific antiviral activity was noted for 5a,b, 7a,b, and 16a,b against any of the viruses tested; dibromodiene 5b proved cytotoxic at a concentration ≥6.7 μM and cytostatic at ≥11 μM, while dienoic esters 16a,b showed activity against both varicella-zoster virus (at 10 μM, 16a) and cytomegalovirus (at 10 μM, 16a; 18 μM, 16b). |
