Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities |
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| Authors: | Yusuke Hanaki Ryo C. Yanagita Takahiro Sugahara Misako Aida Harukuni Tokuda Nobutaka Suzuki |
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| Affiliation: | 1. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan;2. Faculty of Agriculture, Department of Applied Biological Science, Kagawa University, Kagawa, Japan;3. Center for Quantum Life Sciences, Department of Chemistry, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Japan;4. Department of Complementary and Alternative Medicine, Clinical R &5. D, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan |
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| Abstract: | Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (3), in which the C-1 ester group was replaced with an amide group, to improve chemical stability in vivo. Unfortunately, 3 exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10?4 M. A conformational analysis and density functional theory calculations indicated that the stable conformation of 3 differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (1, 2) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10?4 M, 3 may be an inactive control to identify the target proteins of aplogs. |
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| Keywords: | aplysiatoxin anti-proliferative protein kinase C tumor promoter |
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