title: Remarkable stereospecific conjugate additions to the Hsp90 inhibitor celastrol.
abstract: Celastrol, an important natural product and Hsp90 inhibitor with a wide range of biological and medical activities and broad use as a biological probe, acts by an as yet undetermined mode of action. It is known to undergo Michael additions with biological sulfur nucleophiles. Here it is demonstrated that nucleophiles add to the pharmacophore of celastrol in a remarkable stereospecific manner. Extensive characterization of the addition products has been obtained using NMR spectrometry, nuclear Overhauser effects, and density functional theory to determine facial selectivity and gain insight into the orbital interactions of the reactive centers. This stereospecificity of celastrol may be important to its protein target selectivity.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, USA.
authors.forename: Lada
authors.initials: L
authors.lastname: Klaić
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trippier
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D053978:Pentacyclic Triterpenes; D011789:Quantum Theory; D013237:Stereoisomerism; D029757:Tripterygium / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol
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