期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 3, 页码 292-297出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00299
关键词
ROS-activatable prodrug; ATF6 activation; ischemia-reperfusion injury; Cyp1A2
资金
- Welch Foundation [W-1984-20190330, W-0031]
- American Chemical Society Petroleum Research Fund [57370-UNI7]
- National Science Foundation [CHE-1726441]
- Arnold and Mabel Beckman Foundation
- San Antonio Area Foundation
- Trinity University
- American Heart Association [17PRE33670796]
- National Institutes of Health [R01 HL135893, R01 HL75573, R01 HL104535, 1F31HL140850]
- Rees-Stealy Research Foundation
- Inamori Foundation
- ARCS Foundation, Inc., San Diego Chapter
- San Diego State University (SDSU) Heart Institute
We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for the selective delivery of 147, a small molecule ATF6 activator, for ischemia/reperfusion injury. ROS-activatable prodrug 1 and a negative control unable to release free drug were synthesized and examined for peroxide-mediated activation. Prodrug 1 blocks activity of 147 by its inability to undergo metabolic oxidation by ER-resident cytochrome P450 enzymes such as Cyp1A2, probed directly here for the first time. Biological evaluation of ROS-activatable prodrug 1 in primary cardiomyocytes demonstrates protection against peroxide-mediated toxicity and enhances viability following simulated I/R injury. The ability to selectively target ATF6 activation under diseased conditions establishes the potential for localized stress-responsive signaling pathway activation as a therapeutic approach for I/R injury and related protein misfolding maladies.
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