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

• Published in: Journal of medicinal chemistry Vol. 59; no. 23; pp. 10642 - 10660
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-12-2016
• Subjects: Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - pharmacology; Dose-Response Relationship, Drug; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Molecular Dynamics Simulation; Molecular Structure; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01271

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.