Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
| Autor: | Ahmed T. Negmeldin, Christin L. Hanigan, L. M. Viranga Tillekeratne, Robert A. Casero, Jehad Almaliti, Ayad A. Al-Hamashi, Mary Kay H. Pflum, Lalith Perera |
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| Rok vydání: | 2016 |
| Předmět: |
Conformational change
Stereochemistry Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Chemical synthesis Histone Deacetylases Article Structure-Activity Relationship chemistry.chemical_compound Depsipeptides Drug Discovery Humans Structure–activity relationship Depsipeptide chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Thiazoline Combinatorial chemistry 0104 chemical sciences Amino acid Histone Deacetylase Inhibitors Thiazoles Molecular Medicine Histone deacetylase Selectivity |
| Zdroj: | Journal of Medicinal Chemistry. 59:10642-10660 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 sp2at 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. |
| Databáze: | OpenAIRE |
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