Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90

Dutton, Bridie L.; Kitson, Russell R.A.; Parry-Morris, Sarah; Roe, S. Mark; Prodromou, Chrisostomos; Moody, Christopher J.

Abstract

A series of macrolactam analogues of the naturally occurring resorcylic acid lactone radicicol have been synthesised from methyl orsellinate in 7 steps, involving chlorination, protection of the two phenolic groups, and hydrolysis to the benzoic acid. Formation of the dianion and quenching with a Weinreb amide results in acylation of the toluene methyl group that is followed by amide formation and ring closing metathesis to form the macrocyclic lactam. Final deprotection of the phenolic groups gives the desired macrolactams whose binding to the N-terminal domain of yeast Hsp90 was studied by isothermal titration calorimetry and protein X-ray crystallography.

Citation

Dutton, B. L., Kitson, R. R., Parry-Morris, S., Roe, S. M., Prodromou, C., & Moody, C. J. (2014). Synthesis of macrolactam analogues of radicicol and their binding to heat shock protein Hsp90. Organic and Biomolecular Chemistry, 12(8), https://doi.org/10.1039/C3OB42211A

• Journal Article Type: Article
• Acceptance Date: Jan 9, 2014
• Online Publication Date: Jan 10, 2014
• Publication Date: Feb 28, 2014
• Deposit Date: Jul 30, 2014
• Publicly Available Date: Jul 30, 2014
• Journal: Organic and Biomolecular Chemistry
• Print ISSN: 1477-0520
• Electronic ISSN: 1477-0539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 8
• DOI: https://doi.org/10.1039/C3OB42211A
• Public URL: https://nottingham-repository.worktribe.com/output/722644
• Publisher URL: http://pubs.rsc.org/en/Content/ArticleLanding/2014/OB/c3ob42211a#!divAbstract
• Contract Date: Jul 30, 2014