ABSTRACT
Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.
Subject(s)
Depsipeptides/chemistry , Depsipeptides/pharmacology , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Repressor Proteins/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Crystallography, X-Ray , Cyanobacteria/chemistry , Histone Deacetylases/chemistry , Humans , Models, Molecular , Repressor Proteins/chemistryABSTRACT
We achieved the stereoselective syntheses of two different structural patterns corresponding to the enantiomers of the marine natural products abudinol B and muzitone, by developing two-directional tandem biomimetic cyclizations of polyepoxides of squalene analogues in which one alkene was functionalized as an enolsilane. In the course of this work, we demonstrated that the structure of muzitone was misassigned.
Subject(s)
Biomimetic Materials/chemical synthesis , Triterpenes/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Biomimetic Materials/chemistry , Cyclization , Molecular Structure , Stereoisomerism , Triterpenes/chemistryABSTRACT
Squalene tetraepoxide, a putative biosynthetic precursor to a variety of oxacyclic triterpenoid natural products, has been efficiently synthesized by anionic coupling of two farnesol-derived diepoxides, which have arisen from electronic control of the regioselectivity in organocatalytic enantioselective epoxidations.
Subject(s)
Squalene/analogs & derivatives , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , Squalene/chemical synthesis , Squalene/chemistry , StereoisomerismABSTRACT
1,5-D-mannoseptanosyl di- and trisaccharide ring-size isomers of the corresponding mannopyranosyl oligosaccharides have been prepared. Remarkably, these compounds show no inhibition of the alpha-mannosidase-catalyzed hydrolysis of p-nitrophenyl-alpha-D-mannopyranoside.
