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
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- 巻
- 22
- 号
- 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
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- 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
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- DOI : 10.3390/molecules22040631
- ISSN : 1420-3049
- ORCIDのPut Code : 31937821
- Web of Science ID : WOS:000404517800129