Concise syntheses of the abyssinones and discovery of new inhibitors of prostate cancer and MMP-2 expression.
Hydrogen-bonding catalysis is an emerging field that facilitates rapid access to medicinally relevant enantioenriched small molecules. Here, we report the first asymmetric total syntheses of four members of the abyssinone class of natural products (I, II, III, and IV 4´-OMe) via quinine- or quinidine-derived thiourea-catalyzed intramolecular conjugate additions of β-keto ester alkylidenes. This concise strategy includes a tandem deprotection/decarboxylation final step that delivers all four natural products and their corresponding antipodes. A preliminary evaluation of all of these small molecules against a metastatic human prostate cancer cell line has identified that these compounds selectively and differentially inhibit cell growth and downregulate the expression of matrix metalloproteinase-2 (MMP-2) at non-toxic concentrations.
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, Silverman Hall, Evanston, Illinois 60208.
Rebecca L
RL
Farmer
Margaret M
MM
Biddle
Antoinette E
AE
Nibbs
Xiaoke
X
Huang
Raymond C
RC
Bergan
Karl A
KA
Scheidt