Total synthesis of nucleobase-modified adenophostin A mimics

The adenophostins exhibit approximately 10-100 times higher receptor bindin g and Ca2+ mobilising potencies in comparison with the natural second messe nger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3]. Despite many synth etic attempts to determine the minimal structural requirement for this unus ual behaviour of the adenophostins, few related simplified analogues displa ying higher activity than that of Ins(1.4,5)P-3 have been reported. However , biological evaluation of such analogues has revealed that one of the key factors for the enhanced biological activity is the adenine moiety. To furt her understand the effect that the adenine base has upon the activity of th e adenophostins, congeners in which this functionality is replaced by uraci l, benzimidazole, 2-methoxynaphthalene, 4-methylanisole and 4-methylnaphtha lene using the common intermediate 1,2-di-O-acetyl-5-O-benzyl-3-O-(3,4-di-O -acetyl-2,6-di-O-benzyl-alpha -D-glucopyranosyl)-ribofuranose have been syn thesised using a base replacement strategy. The synthesis of the uracil and benzimidazole analogues was achieved using the Vorbruggen condensation pro cedure. The 1'-C-glycosidic analogues were prepared using Friedel-Crafts ty pe C-aryl glycosidation reactions. Phosphate groups were introduced using t he phosphoramidite method with subsequent removal of all-benzyl protecting groups by catalytic hydrogenation or catalytic hydrogen transfer. Apart fro m one analogue with an alpha -glycosidic linkage all compounds were more po tent than Ins(1,4,5)P-3 and most tended more towards adenophostin in activi ty. These analogues will be valuable tools to unravel the role that the ade nine moiety plays in the potent activity of the adenophostins and demonstra te that this strategy is effective at producing highly potent ligands.