Remarkable Stereospecific Conjugate Additions to the Hsp90 Inhibitor Celastrol

• Published in: Journal of the American Chemical Society Vol. 133; no. 49; pp. 19634 - 19637
• Main Authors: Klaić, Lada, Trippier, Paul C, Mishra, Rama K, Morimoto, Richard I, Silverman, Richard B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2011; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Magnetic Resonance Spectroscopy; Models, Molecular; Physical Sciences; Quantum Theory; Science & Technology; Stereoisomerism; Tripterygium - chemistry; Triterpenes - chemistry; Triterpenes - pharmacology; PRISTIMERIN; COMPLEX; ACID; ANTIOXIDANT; HEAT-SHOCK; CHAPERONE; AGGREGATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja208359a

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.