As part of an effort to enhance the cellular activity of balanol analogs 2 and 3, we prepared a series of benzophenone ester analogs of varying steric size and hydrolytic stability. These were evaluated for protein kinase C inhibitory activity, with the results showing that both small alkyl esters and the pivaloyloxymethyl ester analogs displayed large increases in cellular PKC inhibition.Balanol ((-)-1), an unusual metabolite produced by the fungus Verticillium balanoides, was recently isolated and found to be a potent inhibitor of protein kinase C with activity in low nanomolar concentrations. 1 Protein kinase C (PKC) plays a key role in cell growth, metabolism and differentiation and is therefore implicated in several diseases involving these processes. 2 Our study of balanol and related analogs sought to develop a novel balanol analog with therapeutic utility.Studies on structure / activity relationships revealed the importance of the carboxylic acid group for PKC inhibitory activity. 3 However, it was thought that the hydrophilic nature of this group contributed to the lack of activity displayed by balanol in cellular assays. Therefore, a series of acid replacements, namely esters, were synthesized in an attempt to enhance the bioavailability of the compounds by increasing their hydrophobicity.Early in our balanol investigations two azepine replacements, a pyrrolidine ring and cyclopentane ring, were found to give analogs (2 and 3) which displayed comparable PKC inhibitory activity to balanol. 4 These ring systems were used in the ester series reported here for their ease of synthesis over the azepine ring.