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Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90

Nature Chemistry volume 5, pages 307314 (2013) | Download Citation

Abstract

The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, the toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. Here, we report an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.

  • Compound C29H40N2O9

    Geldanamycin

  • Compound C31H43N3O8

    Tanespimycin

  • Compound C32H48N4O8

    Alvespimycin

  • Compound C31H43N3O8

    17-Azetidinyl geldanamycin

  • Compound C29H39IN2O9

    19-Iodogeldanamycin

  • Compound C30H42N2O9

    19-Methylgeldanamycin

  • Compound C31H42N2O9

    19-Vinylgeldanamycin

  • Compound C35H44N2O9

    19-Phenylgeldanamycin

  • Compound C36H46N2O10

    19-(4-Methoxyphenyl)geldanamycin

  • Compound C35H43FN2O9

    19-(4-Fluorophenyl)geldanamycin

  • Compound C39H51N3O10

    19-(4-Morpholinophenyl)geldanamycin

  • Compound C34H43N3O9

    19-(Pyridin-2-yl)geldanamycin

  • Compound C33H42N2O10

    19-(Furan-2-yl)geldanamycin

  • Compound C33H42N2O9S

    19-(Thiophen-2-yl)geldanamycin

  • Compound C32H45N3O8

    19-Methyl-17-allylaminogeldanamycin

  • Compound C37H47N3O8

    19-Phenyl-17-allylaminogeldanamycin

  • Compound C38H49N3O9

    19-(4-Methoxyphenyl)-17-allylaminogeldanamycin

  • Compound C37H46FN3O8

    19-(4-Fluorophenyl)-17-allylaminogeldanamycin

  • Compound C41H54N4O9

    19-(4-Morpholinophenyl)-17-allylaminogeldanamycin

  • Compound C35H45N3O9

    19-(Furan-2-yl)-17-allylaminogeldanamycin

  • Compound C35H45N3O8S

    19-(Thiophen-2-yl)-17-allylaminogeldanamycin

  • Compound C33H50N4O8

    19-Methyl-17-dimethylaminoethylaminogeldanamycin

  • Compound C38H52N4O8

    19-Phenyl-17-dimethylaminoethylaminogeldanamycin

  • Compound C39H54N4O9

    19-(4-Methoxyphenyl)-17-dimethylaminoethylaminogeldanamycin

  • Compound C38H51FN4O8

    19-(4-Fluorophenyl)-17-dimethylaminoethylaminogeldanamycin

  • Compound C42H59N5O9

    19-(4-Morpholinophenyl)-17-dimethylaminoethylaminogeldanamycin

  • Compound C36H50N4O9

    19-(Furan-2-yl)-17-dimethylaminoethylaminogeldanamycin

  • Compound C36H50N4O8S

    19-(Thiophen-2-yl)-17-dimethylaminoethylaminogeldanamycin

  • Compound C35H49N3O12S

    (R)-Methyl 2-acetamido-3-(((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-9-(carbamoyloxy)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-21-yl)thio)propanoate

  • Compound C37H52N4O11S

    (R)-Methyl 2-acetamido-3-(((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(allylamino)-9-(carbamoyloxy)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-21-yl)thio)propanoate

  • Compound C38H57N5O11S

    (R)-Methyl 2-acetamido-3-(((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-9-(carbamoyloxy)-19-((2-(dimethylamino)ethyl) amino)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-21-yl)thio)propanoate

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Acknowledgements

The authors acknowledge support from the Parkinson's Disease Society UK (R.R.A.K. and C.J.M.). The work was also supported by the National Institutes of Health (NIH grants CA51210 and ES018943; D.R., D.S., C-H.C. and R.X.). The authors thank S. Aslam and K. Butler for help with NMR studies, and S. Young (University of Nottingham, ICPMS), M. Cooper and G. Coxhill (University of Nottingham, mass spectrometry) for technical assistance.

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Affiliations

  1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK

    • Russell R. A. Kitson
    • , Huw E. L. Williams
    • , Adrienne L. Davis
    • , William Lewis
    •  & Christopher J. Moody
  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045, USA

    • Chuan-Hsin Chang
    • , Rui Xiong
    • , Donna L. Dehn
    • , David Siegel
    •  & David Ross
  3. Genome Damage and Stability Centre, Science Park Road, University of Sussex, Falmer, Brighton BN1 9RQ, UK

    • S. Mark Roe
    •  & Chrisostomos Prodromou

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Contributions

D.R. and C.J.M. jointly conceived the project, and directed the biology and chemistry, respectively. R.R.A.K. was responsible for the design and execution of the chemistry. NMR studies and molecular modelling were carried out by R.R.A.K., H.E.L.W. and A.L.D., and W.L. carried out small-molecule X-ray crystallography. The biological studies were co-directed by D.S., and carried out by C-H.C., D.L.D. and R.X. Protein crystallography was directed by C.P. and carried out by C.P. and S.M.R. All authors contributed to the preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chrisostomos Prodromou or David Ross or Christopher J. Moody.

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    Crystallographic data for compound 13

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https://doi.org/10.1038/nchem.1596

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