Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue.
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 sp3to 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.
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.|Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan , Amman, 11942, Jordan.
Jehad
J
Almaliti
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.
Ayad A
AA
Al-Hamashi
Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.
Ahmed T
AT
Negmeldin
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.
Christin L
CL
Hanigan
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.
Lalith
L
Perera
Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.
Mary Kay H
MK
Pflum
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.
Robert A
RA
Casero
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.
L M Viranga
LM
Tillekeratne
D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D013844:Thiazoles; C527895:largazole; D006655:Histone Deacetylases