Protein kinase C ligands based on tetrahydrofuran templates containing a new set of phorbol ester pharmacophores

A series of substituted tetrahydrofurans with an embedded glycerol backbone carrying additional tetrahydrofuranylideneacetate or tetrahydrofuranylacet ate motifs were grouped into four distinct templates (I-IV) according to st ereochemistry. The compounds were designed to mimic three essential pharmac ophores (C-3-C=O, C-20-OH and C-13-C=O) of the phorbol esters according to a new, revised model. The tetrahydrofuran ring was constructed from glycidy l 4-methoxyphenyl ether, and the structures of the isomeric templates were assigned by NMR spectroscopy, including NOE. The binding affinity for prote in kinase C (PKC) was assessed in terms of the ability of the ligands to di splace bound [H-3-20]phorbol 12,13-dibutyrate (PDBU) from a recombinant alp ha isozyme of PKC. Geometric Z- and E-isomers (1 and 3, respectively) conta ining a tetrahydrofuranylideneacetate motif were the most potent ligands wi th identical K-i values of 0.35 mu M. Molecular modeling studies of the fou r templates showed that the rms values when fitted to a prototypical phorbo l 12,13-diacetate ester correlated inversely with affinities in the followi ng order: I approximate to II > III > TV. These compounds represent the fir st generation of rigid glycerol templates seeking to mimic the binding of t he C-13-C=O of the phorbol esters. The binding affinities of the most poten t compounds are in the same range of the diacylglycerols (DAGs) despite the lack of a phorbol ester C-9-OH pharmacophore surrogate. This finding confi rms that mimicking the binding of the C-13-C=O pharmacophore of phorbol is a useful strategy. However, since the C-9-OH and C-13-C=O in the phorbol es ters appear to form an intramolecular hydrogen bond that functions as a com bined pharmacophore, it is possible the lack of this combined motif in the target templates restricts the compounds from reaching higher binding affin ities.