Synthesis and structure&ndash;activity studies of simplified analogues of aplysiatoxin with antiproliferative activity like bryostatin-1

Irie, Kazuhiro; Kikumori, Masayuki; Kamachi, Hiroaki; Tanaka, Keisuke; Murakami, Akira; Yanagita, Ryo C.; Tokuda, Harukuni; Suzuki, Nobutaka; Nagai, Hiroshi; Suenaga, Kiyotake; Nakagawa, Yu

doi:10.1351/PAC-CON-11-08-22

Pure Appl. Chem., 2012, Vol. 84, No. 6, pp. 1341-1351

http://dx.doi.org/10.1351/PAC-CON-11-08-22

Published online 2012-02-08

Synthesis and structure–activity studies of simplified analogues of aplysiatoxin with antiproliferative activity like bryostatin-1

Kazuhiro Irie^1,2*, Masayuki Kikumori¹, Hiroaki Kamachi¹, Keisuke Tanaka¹, Akira Murakami¹, Ryo C. Yanagita^3,1, Harukuni Tokuda⁴, Nobutaka Suzuki⁴, Hiroshi Nagai⁵, Kiyotake Suenaga⁶ and Yu Nakagawa^1,7

¹ Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
² Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8502, Japan
³ Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Kagawa 761-0195, Japan
⁴ Department of Complementary and Alternative Medicine, Clinical R&D, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
⁵ Tokyo University of Marine Science and Technology, Tokyo 108-8477, Japan
⁶ Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan
⁷ Synthetic Cellular Chemistry Laboratory, Advanced Science Institute, RIKEN, Saitama 351‑0198, Japan

Abstract: Protein kinase C (PKC) isozymes are promising targets for anticancer therapy. Bryostatin-1 (bryo-1), a unique PKC activator with little tumor-promoting activity, is currently in clinical trials for the treatment of cancer. However, its limited availability from natural sources and its synthetic complexity have hampered studies of its mode of action and structural optimization as a therapeutic agent. The development of synthetically more accessible compounds with bryo-1-like activities is thus needed. Recently, we developed a simple and less lipophilic analogue of tumor-promoting aplysiatoxin (ATX) (aplog-1) as a promising lead for bryo-1-like anticancer drugs. Structure–activity studies suggested that local hydrophobicity around the spiroketal moiety of aplog-1 is a crucial determinant of its antiproliferative activity. The hydrophobic analogue (12,12-dimethyl-aplog-1) displayed more potent antiproliferative activity. Moreover, it showed little tumor-promoting activity and even suppressed the tumor promotion by 12-O-tetradecanoylphorbol 13-acetate (TPA) in vivo and in vitro. Aplog-1 and bryo-1 bound selectively to novel PKC isozymes (δ, η, and θ) while tumor promoters bound to both conventional and novel PKC isozymes. These results suggest that the unique biological activities of aplog-1 and bryo-1 are ascribable in part to the ability to bind to PKCδ, but weak binding to conventional PKC isozymes might also be important.