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

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

研究成果: Article査読

10 被引用数 (Scopus)

抄録

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 hydro -phobicity 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.

本文言語English
ページ(範囲)1341-1351
ページ数11
ジャーナルPure and Applied Chemistry
84
6
DOI
出版ステータスPublished - 2012

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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