Downloads: 440

Files in This Item:
File Description SizeFormat 
PAC-CON-11-08-22.pdf718.47 kBAdobe PDFView/Open
Title: Synthesis and structure–activity studies of simplified analogues of aplysiatoxin with antiproliferative activity like bryostatin-1
Authors: Irie, Kazuhiro  kyouindb  KAKEN_id  orcid (unconfirmed)
Kikumori, Masayuki
Kamachi, Hiroaki
Tanaka, Keisuke
Murakami, Akira  KAKEN_id
Yanagita, Ryo C.
Tokuda, Harukuni
Suzuki, Nobutaka
Nagai, Hiroshi
Suenaga, Kiyotake
Nakagawa, Yu
Author's alias: 入江, 一浩
Keywords: antiproliferative activity
antitumor activity
bioactive molecules
biological activity
organic chemistry
organic synthesis
phorbol ester
protein kinase C
tumor promoter
Issue Date: 2012
Publisher: International Union of Pure and Applied Chemistry
Journal title: Pure and Applied Chemistry
Volume: 84
Issue: 6
Start page: 1341
End page: 1351
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.
Rights: © 2012 IUPAC.
DOI(Published Version): 10.1351/PAC-CON-11-08-22
Appears in Collections:Journal Articles

Show full item record

Export to RefWorks

Export Format: 

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.