TY - JOUR
T1 - Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury
AU - Palmer, Jonathan E.
AU - Brietske, Breanna M.
AU - Bate, Tyler C.
AU - Blackwood, Erik A.
AU - Garg, Manasa
AU - Glembotski, Christopher C.
AU - Cooley, Christina B.
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/3/12
Y1 - 2020/3/12
N2 - 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.
AB - 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.
KW - ATF6 activation
KW - Cyp1A2
KW - ROS-activatable prodrug
KW - ischemia-reperfusion injury
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U2 - 10.1021/acsmedchemlett.9b00299
DO - 10.1021/acsmedchemlett.9b00299
M3 - Article
AN - SCOPUS:85074748037
SN - 1948-5875
VL - 11
SP - 292
EP - 297
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 3
ER -