Activation of sulfonate ester based matrix metalloproteinase proinhibitors by hydrogen peroxide.
This study details the development of matrix metalloproteinase inhibitor prodrugs (proMMPi) that are activated in the presence of reactive-oxygen species (ROS). Conventional matrix metalloproteinase inhibitors (MMPi) utilize a zinc-binding group (ZBG) that chelates to the catalytic zinc(II) ion of matrix metalloproteinases (MMPs) to inhibit their activity. To create ROS-sensitive prodrugs, sulfonate esters were used as a protecting group for the ZBG to block their metal binding ability. Surprisingly, these sulfonate esters were found to be cleaved by H(2)O(2) only when the ZBG contained an N-oxide donor atom moiety. Sulfonate ester derivatives of full-length MMPi based on these ROS-triggerable systems were synthesized. It was found that proMMPi with sulfonate ester protecting groups showed relatively high rates of cleavage in the presence of H(2)O(2) to release the active MMPi. In vitro MMP inhibition studies confirmed a significant increase in inhibitory activity of proMMPi upon addition of H(2)O(2), demonstrating the use of sulfonate esters to act as cleavable triggers for ROS-activated prodrugs.
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.
Kevin B
KB
Daniel
Jody L
JL
Major Jourden
Kimberly E
KE
Negoescu
Seth M
SM
Cohen
D004789:Enzyme Activation / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D011355:Prodrugs; D011480:Protease Inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; D011355:Prodrugs; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide