title: Design and synthesis of 8-octyl-benzolactam-V9, a selective activator for protein kinase C epsilon and eta.
abstract: Conventional (alpha, betaI, betaII, gamma) and novel (delta, epsilon, eta, theta) 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 PKC epsilon and eta from the cytoplasm to the plasma membrane of HeLa cells at 1 microM, whereas other PKC isozymes did not respond even at 10 microM. These results indicate that 4 could be a selective activator for PKC epsilon and eta.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.forename: Hajime
authors.initials: H
authors.lastname: Ohigashi
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Tsuda
authors.forename: Kaori
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
mesh_terms: D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport
chemical_list: C510634:8-octylbenzolactam-V9; D007527:Isoenzymes; D007769:Lactams; D011493:Protein Kinase C