Function oriented synthesis: preparation and initial biological evaluation of new A-ring-modified bryologs

The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7-2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A-ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function.