COMPARISON BETWEEN INHIBITION OF PROTEIN-KINASE-C AND ANTAGONISM OF CALMODULIN BY TAMOXIFEN ANALOGS

A variety of analogues of tamoxifen were tested for inhibition of protein kinase C (PKC) activity in MCF-7 breast cancer cells. These results were compared with the calmodulin antagonism exhibited by the analogues as measured by inhibition of calmodulin-dependent cyclic AMP phosphodiesterase. The same structural features that enhanced PKC inhibition also led to an increase in calmodulin antagonism, namely 4-iodination and elongation of the basic side-chain. The most potent analogue has a 4-iodine substituent and eight carbon atoms in its basic side-chain with IC50 values of 38 mu M for PKC inhibition and 0.3 mu M for calmodulin antagonism, which compares with 92 and 6.8 mu M, respectively, for tamoxifen. Some selectivity was achieved with a ring-fused analogue that retained the potency of tamoxifen as a PKC inhibitor, but lacked calmodulin antagonism.