Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole-Modified Cyclic Tetrapeptides

Authors

  • W. Seth Horne Dr.,

    1. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858-784-2798
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    • These authors contributed equally to this work.

  • Christian A. Olsen Dr.,

    1. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858-784-2798
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    • These authors contributed equally to this work.

  • John M. Beierle,

    1. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858-784-2798
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  • Ana Montero Dr.,

    1. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858-784-2798
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  • M. Reza Ghadiri Prof. Dr.

    1. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858-784-2798
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  • We thank Dr. Dee Huang and Dr. Laura Pasternack for assistance with NMR spectroscopy, Dr. Sheo Singh for providing the coordinates of the published NMR structure of apicidin in [D5]pyridine, Dr. Michael Kranz for providing the coordinates of the calculated lowest-energy conformations of apicidin, Dr. Michael Pique for assistance in the preparation of the frontispiece graphics, and Dr. L. J. Leman for assistance in manuscript preparation. We acknowledge the National Science Foundation (W.S.H.) and NASA Earth and Space Science Fellowship Program (grant NNX07AR35H; J.M.B.) for predoctoral fellowships. A.M. thanks the Spanish Ministry for Science and Education for a Fulbright/MEC postdoctoral fellowship. C.A.O. thanks the Lundbeck Foundation and the Danish Research Council for Technology and Production Sciences (274-06-0317) for postdoctoral fellowships, and the Danish Independent Research Council for a Young Researcher's Award. This research was supported in part by a grant from the National Institute of General Medical Sciences (GM52190) and by the Skaggs Institute for Chemical Biology. HDAC=histone deacetylase.

Abstract

Besser als das Original: Neuartige Analoga von Apicidin, einem cyclischen Tetrapeptidinhibitor der Histon-Desacetylase (HDAC), enthalten ein 1,4- oder 1,5-disubstituiertes 1,2,3-Triazol anstelle einer Gerüst-Amidbindung, um die entsprechende Bindung in trans- oder cis-Konfiguration zu fixieren. So ließ sich die Bindungsaffinität unterschiedlicher Peptidkonformationen (siehe Bild) untersuchen. Ein Analogon erwies sich in einigen Fällen als ein dem Apicidin überlegener HDAC-Inhibitor.

original image

Ancillary