Substituted quinolines as noncovalent proteasome inhibitors.
Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
Tanner J
TJ
McDaniel
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
Theresa A
TA
Lansdell
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
Amila A
AA
Dissanayake
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
Lauren M
LM
Azevedo
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
Jacob
J
Claes
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States. Electronic address: Odom@chemistry.msu.edu.
Aaron L
AL
Odom
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States. Electronic address: Tepe@chemistry.msu.edu.
Jetze J
JJ
Tepe
D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D061988:Proteasome Inhibitors; D011804:Quinolines; D046988:Proteasome Endopeptidase Complex
Inhibitors; Noncovalent; Proteasome; Quinolines