Structure-activity studies at position 27 of aplog-1, a simplified analog of debromoaplysiatoxin with anti-proliferative activity

Aplog-1, a simplified analog of debromoaplysiatoxin with anti-proliferative activity, bound to and activated protein kinase Cδ (PKCδ), that is involved in tumor suppression and apoptosis. To examine the contribution of PKCδ to the anti-proliferative activity of aplog-1, we synthesized 27-methyl and 27-methoxy derivatives that differed in the ability to activate PKCδ. Activators of PKCδ like aplog-1 and 27-(R)-Me-aplog-1 strongly inhibited the growth of several cancer cell lines. On the other hand, 27-(S)-Me-aplog-1 and 27-O-Me-aplog-1 without the ability to activate PKCδ, exhibited only weak growth inhibitory activity against these cell lines. These results suggest indirectly that the activation of PKCδ might be involved in the anti-proliferative activity of aplog-1 against aplog-sensitive cancer cell lines.

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