EFFECT OF ALTERATION OF THE HETEROCYCLIC NUCLEUS OF ILV ON ITS ISOFORM SELECTIVITY FOR PKC - PALLADIUM-CATALYZED ROUTE TO BENZOFURAN ANALOGS OF ILV

The discovery of isoform-selective modulators of protein kinase C (PKC ) appears worthwhile in further defining the roles of the individual P KC isoforms in cell type-specific processes. In comparison with the ph orbol esters, little information is available regarding the isoform se lectivity of the teleocidin family. Blumberg has reported recently tha t 7-n-octylindolactam V exhibits little if any selectivity for the iso forms tested. In order to probe the possibility of developing isotype- selective agents based on the indolactam V (ILV) structure, we sought to explore replacement of the indole nucleus by a benzofuran ring. Her ein we describe a novel palladium-catalyzed route to four benzofuran a nalogues 11a-d of ILV together with details of their isoform selectivi ty. Of considerable interest is the unexpected finding that this subtl e N to O structural change leads to a compound (11b) that is modestly more like 12,13-dibutyrate phorbol and less like n-octyl-ILV in its pa ttern of activity. Moreover, the effect of introducing an additional s tereocenter at C-14 into these benzofurans was explored, and a clear p reference for R-stereochemistry at the C-14 center of the teleocidin f amily was found, thus providing additional verification of previously published structural correlations between the families of PKC activato rs. Overall, the present findings provide an important new direction i n the quest for isoform-selective activators of PKC.