Synthesis of modified ingenol esters

Synthetic protocols for the manipulation of the polyhydroxylated southern r egion of ingenol (1a) were developed, and a series of isosteres of the anti cancer compound ingenol 3,20-dibenzoate (1b) was prepared. The biological e valuation of these compounds showed that cytotoxicity was relatively tolera nt to changes at C-20, while PKC activation was markedly affected by these modifications. These data suggest that chemical manipulation can effectivel y dissect cytotoxicity and tumour-promoting activity (or potential) of inge noids, affording more optimal candidates for development, like 20-deoxy-20- fluoroingenol 3,20-dibenzoate (5b). In mild acidic medium, an unexpected vi nylogous retro-pinacol rearrangement of ingenol to a tigliane derivative wa s observed.