Synthesis of hydroxypyrone- and hydroxythiopyrone-based matrix metalloproteinase inhibitors: developing a structure-activity relationship.
The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases. Development of inhibitors to modulate MMP activity has been an active area of investigation for therapeutic development. Hydroxypyrones and hydroxythiopyrones are alternative zinc-binding groups (ZBGs) that, when combined with peptidomimetic backbones, comprise a novel class of MMP inhibitors (MMPi). In this report, a series of hydroxypyrone- and hydroxythiopyrone-based MMPi with aryl backbones at the 2-, 5-, and 6-positions of the hydroxypyrone ring have been synthesized. Synthetic routes for developing inhibitors with substituents at two of these positions (so-called double-handed inhibitors) are also explored. The MMP inhibition profiles and structure-activity relationship of synthesized hydroxypyrones and hydroxythiopyrones have been analyzed. The results here show that the ZBG, the position of the backbone on the ZBG, and the nature of the linker between the ZBG and backbone are critical for MMPi activities.
Yan
Yi-Long
YL
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, United States.
Miller
Melissa T
MT
Cao
Yuchen
Y
Cohen
Seth M
SM
D002352:Carrier Proteins / Q000737:chemistry; D015195:Drug Design; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011753:Pyrones; C017800:zinc-binding protein; D020782:Matrix Metalloproteinases