Design and synthesis of 8-octyl-benzolactam-V9, a selective activator for protein kinase C epsilon and eta

Journal of Medicinal Chemistry
Yu NakagawaNaoaki Saito

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.

References

Feb 1, 1997·Protein Science : a Publication of the Protein Society·J H HurleyY Nishizuka
Jul 26, 2005·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Kazuhiro IrieHajime Ohigashi

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Citations

Nov 7, 2014·Chemical Reviews·Joydip Das, Ghazi M Rahman
May 16, 2007·The Journal of Pharmacology and Experimental Therapeutics·Hao SunGarold S Yost
Nov 2, 2020·Bioorganic & Medicinal Chemistry Letters·Takumi KobayashiKazuhiro Irie
Jul 13, 2013·The Journal of Organic Chemistry·Michele MariGiovanni Piersanti

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