Synthesis, conformation and PKC isozyme surrogate binding of new lactone analogues of benzolactam-V8s

To investigate the role of the amide hydrogen of benzolactam-V8s () on protein kinase C (PKC) isozyme binding, new lactone analogues of benzolactam-V8s with hydrophobic side chains at positions 8 and/or 9 () were synthesized. The PKC binding affinities of 8- and 9-decylbenzolactone-V8 (,) were much lower than those of 8- and 9-decylbenzolactam-V8 (,), respectively, indicating that the amide hydrogen of benzolactam-V8s plays a critical role in PKC binding. 8-Decylbenzolactam-V8 () showed lower binding affinities to all PKC isozymes compared with those of 9-decylbenzolactam-V8 (). The binding affinities of 8-substituted benzolactones (,,) were also lower than those of 9-decylbenzolactone-V8 (), but their PKC isozyme selectivity was higher than those of , and . 8-Decybenzolactone-V8 () exhibited the most significant η-C1B selectivity among the four benzolactones () synthesized in this study.