Design and Synthesis of 8-Octyl-benzolactam-V9, a Selective Activator for Protein Kinase Cε and η

Conventional (α, βI, βII, γ) and novel (δ, e, η, θ) protein kinase C (PKC) isozymes are main targets of tumor promoters, such as phorbol esters and indolactam-V (ILV). We have recently found that 1-hexyl derivatives of indolinelactam-V (2, 3), in which the indole ring of ILV was replaced with the indoline ring, showed a binding preference for novel PKCs over conventional PKCs. To develop a new ILV analogue displaying increased synthetic accessibility and improved binding selectivity for novel PKCs, we have designed 8-octyl-benzolactam-V9 (4), a simple analogue without the pyrrolidine moiety of 2 and 3. Compound 4 showed significant binding selectivity for isolated C1B domains of novel PKCs. Moreover, 4 translocated PKCe and η from the cytoplasm to the plasma membrane of HeLa cells at 1 μM, whereas other PKC isozymes did not respond even at 10 μM. These results indicate that 4 could be a selective activator for PKCe and η.