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

Jehad Almaliti, Ayad A. Al-Hamashi, Ahmed T. Negmeldin, Christin L. Hanigan, Lalith Perera, Mary Kay H. Pflum, Robert A. Casero, L. M.Viranga Tillekeratne

Research output: Contribution to journalArticle

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-a-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.

Original languageEnglish (US)
Pages (from-to)10642-10660
Number of pages19
JournalJournal of medicinal chemistry
Volume59
Issue number23
DOIs
StatePublished - Dec 8 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Almaliti, J., Al-Hamashi, A. A., Negmeldin, A. T., Hanigan, C. L., Perera, L., Pflum, M. K. H., Casero, R. A., & Tillekeratne, L. M. V. (2016). Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue. Journal of medicinal chemistry, 59(23), 10642-10660. https://doi.org/10.1021/acs.jmedchem.6b01271