論文

査読有り 本文へのリンクあり 国際誌
2017年4月

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

Molecules
  • Yusuke Hanaki
  • ,
  • Masayuki Kikumori
  • ,
  • Harukuni Tokuda
  • ,
  • Mutsumi Okamura
  • ,
  • Shingo Dan
  • ,
  • Naoko Adachi
  • ,
  • Naoaki Saito
  • ,
  • Ryo C. Yanagita
  • ,
  • Kazuhiro Irie

22
4
開始ページ
631
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.3390/molecules22040631
出版者・発行元
MDPI AG

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 PKC delta, 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/pi interaction between its side chain and either Met-239 or Pro-241 in the PKC delta-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 PKC delta-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 PKC delta-GFP due to induction by 1-3 were similar.

リンク情報
DOI
https://doi.org/10.3390/molecules22040631 本文へのリンクあり
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000404517800129&DestApp=WOS_CPL
共同研究・競争的資金等の研究課題
天然PKCリガンドによる化学コミュニケーションの統合的理解と医薬品シーズの開発
URL
http://www.mdpi.com/1420-3049/22/4/631 本文へのリンクあり
URL
http://orcid.org/0000-0002-9217-5507
ID情報
  • DOI : 10.3390/molecules22040631
  • ISSN : 1420-3049
  • ORCIDのPut Code : 31937821
  • Web of Science ID : WOS:000404517800129

エクスポート
BibTeX RIS