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

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Depsipeptides
Thiazoles
Histone Deacetylase Inhibitors
Histone Deacetylases
largazole
Amino Acids
Growth

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Almaliti, J., Al-Hamashi, A. A., Negmeldin, A. T., Hanigan, C. L., Perera, L., Pflum, M. K. H., ... 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

Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring : Development of a More Selective and Highly Potent Analogue. / Almaliti, Jehad; Al-Hamashi, Ayad A.; Negmeldin, Ahmed T.; Hanigan, Christin L.; Perera, Lalith; Pflum, Mary Kay H; Casero, Robert A; Tillekeratne, L. M Viranga.

In: Journal of Medicinal Chemistry, Vol. 59, No. 23, 08.12.2016, p. 10642-10660.

Research output: Contribution to journalArticle

Almaliti, J, Al-Hamashi, AA, Negmeldin, AT, Hanigan, CL, Perera, L, Pflum, MKH, Casero, RA & Tillekeratne, LMV 2016, 'Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue', Journal of Medicinal Chemistry, vol. 59, no. 23, pp. 10642-10660. https://doi.org/10.1021/acs.jmedchem.6b01271
Almaliti, Jehad ; Al-Hamashi, Ayad A. ; Negmeldin, Ahmed T. ; Hanigan, Christin L. ; Perera, Lalith ; Pflum, Mary Kay H ; Casero, Robert A ; Tillekeratne, L. M Viranga. / Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring : Development of a More Selective and Highly Potent Analogue. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 23. pp. 10642-10660.
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