Downloads: 175

Files in This Item:
File Description SizeFormat 
molecules22040631.pdf2.56 MBAdobe PDFView/Open
Title: Loss of the Phenolic Hydroxyl Group and Aromaticity from the Side Chain of Anti-Proliferative 10-Methyl-aplog-1, a Simplified Analog of Aplysiatoxin, Enhances Its Tumor-Promoting and Proinflammatory Activities
Authors: Hanaki, Yusuke
Kikumori, Masayuki
Tokuda, Harukuni
Okamura, Mutsumi
Dan, Shingo
Adachi, Naoko
Saito, Naoaki
Yanagita, Ryo C.
Irie, Kazuhiro  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 花木, 祐輔
菊森, 将之
徳田, 春邦
入江, 一浩
Keywords: protein kinase C
C1 domain
Issue Date: 13-Apr-2017
Publisher: MDPI AG
Journal title: Molecules
Volume: 22
Issue: 4
Thesis number: 631
Abstract: Aplysiatoxin (ATX) is a protein kinase C (PKC) activator with potent tumor-promoting activity. In contrast, 10-methyl-aplog-1 (1), a simplified analog of ATX, was anti-proliferative towards several cancer cell lines without significant tumor-promoting and proinflammatory activities. To determine the effects of the phenolic group on the biological activities of 1, we synthesized new derivatives (2, 3) that lack the phenolic hydroxyl group and/or the aromatic ring. Compound 2, like 1, showed potent anti-proliferative activity against several cancer cell lines, but little with respect to tumor-promoting and proinflammatory activities. In contrast, 3 exhibited weaker growth inhibitory activity, and promoted inflammation and tumorigenesis. The binding affinity of 3 for PKCδ, which is involved in growth inhibition and apoptosis, was several times lower than those of 1 and 2, possibly due to the absence of the hydrogen bond and CH/π interaction between its side chain and either Met-239 or Pro-241 in the PKCδ-C1B domain. These results suggest that both the aromatic ring and phenolic hydroxyl group can suppress the proinflammatory and tumor-promoting activities of 1 and, therefore, at least the aromatic ring in the side chain of 1 is indispensable for developing anti-cancer leads with potent anti-proliferative activity and limited side effects. In accordance with the binding affinity, the concentration of 3 necessary to induce PKCδ-GFP translocation to the plasma membrane and perinuclear regions in HEK293 cells was higher than that of 1 and 2. However, the translocation profiles for PKCδ-GFP due to induction by 1–3 were similar.
Rights: © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
DOI(Published Version): 10.3390/molecules22040631
PubMed ID: 28406454
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.