2. Academic Validation
  3. Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

  • J Med Chem. 2016 Dec 8;59(23):10642-10660. doi: 10.1021/acs.jmedchem.6b01271.
Jehad Almaliti 1 2,  Ayad A Al-Hamashi 1,  Ahmed T Negmeldin 3,  Christin L Hanigan 4,  Lalith Perera 5,  Mary Kay H Pflum 3,  Robert A Casero Jr 4,  L M Viranga Tillekeratne 1
Affiliations

Affiliations

  • 1 Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo , 2801, W. Bancroft Street, Toledo, Ohio 43606, United States.
  • 2 Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan , Amman, 11942, Jordan.
  • 3 Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.
  • 4 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine , Bunting/Blaustein Cancer Research Building 1, Room 551, 1650 Orleans Street, Baltimore, Maryland 21231, United States.
  • 5 Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, United States.
PMID: 27809521 DOI: 10.1021/acs.jmedchem.6b01271
Abstract

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

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