Natural product based inhibitors of the thioredoxin-thioredoxin reductase system.
Spiroketal naphthodecalins are readily assembled by Barton's base mediated Ullmann binaphthyl ether coupling, Dakin reactions and hypervalent iodine spirocyclization. The core structures can be further diversified by enone addition and Stille coupling reactions. Nanomolar inhibitors for the Trx/TrxR redox control system were prepared by this approach and compared to series of natural product isolates. Cytotoxicity in MCF-7 cell assays ranged from an IC50 of 1.6 to >100 microM.
Wipf
Peter
P
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. pwipf@pitt.edu
Lynch
Stephen M
SM
Birmingham
Anne
A
Tamayo
Giselle
G
Jiménez
Allan
A
Campos
Nefertiti
N
Powis
Garth
G
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D013879:Thioredoxins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D013141:Spiro Compounds; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase