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Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90.

ABSTRACT: A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (approximately 25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (approximately 100 nM).

SUBMITTER: Wrona IE 

PROVIDER: S-EPMC2906235 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90.

Wrona Iwona E IE   Gozman Alexander A   Taldone Tony T   Chiosis Gabriela G   Panek James S JS  

The Journal of organic chemistry 20100501 9

A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employe  ...[more]

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