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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1341-1351
Number of pages11
JournalPure and Applied Chemistry
Volume84
Issue number6
DOIs
Publication statusPublished - 2012

Fingerprint

Protein Kinase C
Tumors
Proteins
Isoenzymes
Structural optimization
Bioactivity
Carcinogens
bryostatin 1
aplysiatoxin
Acetates
Lead
Availability
Pharmaceutical Preparations

Keywords

  • Antiproliferative activity
  • Antitumor activity
  • Aplysiatoxin
  • Bioactive molecules
  • Biological activity
  • Bryostatin
  • Organic chemistry
  • Organic synthesis
  • Phorbol ester
  • Protein kinase c
  • Structure-activity
  • Tumor promoter

ASJC Scopus subject areas

  • Chemical Engineering(all)
  • Chemistry(all)

Cite this

Synthesis and structure-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.

In: Pure and Applied Chemistry, Vol. 84, No. 6, 2012, p. 1341-1351.

Research output: Contribution to journalArticle

Irie, K, Kikumori, M, Kamachi, H, Tanaka, K, Murakami, A, Yanagita, RC, Tokuda, H, Suzuki, N, Nagai, H, Suenaga, K & Nakagawa, Y 2012, 'Synthesis and structure-activity studies of simplified analogues of aplysiatoxin with antiproliferative activity like bryostatin-1', Pure and Applied Chemistry, vol. 84, no. 6, pp. 1341-1351. https://doi.org/10.1351/PAC-CON-11-08-22
Irie, Kazuhiro ; Kikumori, Masayuki ; Kamachi, Hiroaki ; Tanaka, Keisuke ; Murakami, Akira ; Yanagita, Ryo C. ; Tokuda, Harukuni ; Suzuki, Nobutaka ; Nagai, Hiroshi ; Suenaga, Kiyotake ; Nakagawa, Yu. / Synthesis and structure-activity studies of simplified analogues of aplysiatoxin with antiproliferative activity like bryostatin-1. In: Pure and Applied Chemistry. 2012 ; Vol. 84, No. 6. pp. 1341-1351.
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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 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.",
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AU - Kamachi, Hiroaki

AU - Tanaka, Keisuke

AU - Murakami, Akira

AU - Yanagita, Ryo C.

AU - Tokuda, Harukuni

AU - Suzuki, Nobutaka

AU - Nagai, Hiroshi

AU - Suenaga, Kiyotake

AU - Nakagawa, Yu

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