Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR.
A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an alpha-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.
Lin
Songnian
S
Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Yang
Zhi-Qiang
ZQ
Kwok
Benjamin H B
BH
Koldobskiy
Michael
M
Crews
Craig M
CM
Danishefsky
Samuel J
SJ
D000577:Amides / Q000737:chemistry; D000818:Animals; D002417:Cattle; D003546:Cysteine Endopeptidases; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D010880:Piperidines / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship
D000577:Amides; D009097:Multienzyme Complexes; D010456:Peptides, Cyclic; D010880:Piperidines; C408291:TMC-95A; C408292:TMC-95B; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex