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

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

doi:10.1039/c3ob42211a

Bridie L Dutton, Russell R A Kitson + Show 4 more

Open Access

https://doi.org/10.1039/c3ob42211a

Copy DOI

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.

Highlights

In recent years, the chaperone heat shock protein 90 (Hsp90) has become one of the most attractive and widely studied biological targets for molecular cancer therapeutics.[1, 2] Ubiquitous in eukaryotic cells, Hsp[90] utilises the energy released from ATP-hydrolysis to effect the maturation or activation of client proteins and has been found to play a pivotal role in numerous oncogenic pathways
Significant research efforts have been devoted to discovering and synthesising potent small molecule inhibitors of Hsp[90], a topic which has been the focus of many reviews.[2, 9, 10, 15,16,17,18,19,20,21,22]
Seminal research in this area was centred on the natural products geldanamycin 1,23, 24 a benzoquinone ansamycin polyketide, which has been the subject of previously published research from our group,[25,26,27] and radicicol 2, a resorcylic acid lactone (RAL) first isolated in 1953,28 which is the most potent in vitro Hsp[90] inhibitor found to date (IC50 =20−23 nM).[29,30,31]

Summary

Introduction

The chaperone heat shock protein 90 (Hsp90) has become one of the most attractive and widely studied biological targets for molecular cancer therapeutics.[1, 2] Ubiquitous in eukaryotic cells, Hsp[90] utilises the energy released from ATP-hydrolysis to effect the maturation or activation of client proteins and has been found to play a pivotal role in numerous oncogenic pathways.

Results

Conclusion