title: Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups.
abstract: Several largazole analogues with modified surface recognition cap groups were synthesized and their HDAC inhibitory activities were determined. The C7-epimer 12 caused negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal effect on growth. Although previous studies have shown some degree of tolerance of structural changes at C7 position of largazole, these data show the negative effect of conformational change accompanying change of configuration at this position. Similarly, analogue 16a with D-1-naphthylmethyl side chain at C2 too had negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal effect on growth. In contrast, the L-allyl analogue 16b and the L-1-naphthylmethyl analogue 16c were potent HDAC inhibitors, showing robust induction of global H3 acetylation and significant effect on cell growth. The data suggest that even bulky substituents are tolerated at this position, provided the stereochemistry at C2 is retained. With bulky substituents, inversion of configuration at C2 results in loss of inhibitory activity. The activity profiles of 16b and 16c on Class I HDAC1 vs Class II HDAC6 are similar to those of largazole and, taken together with x-ray crystallography information of HDAC8-largazole complex, may suggest that the C2 position of largazole is not a suitable target for structural optimization to achieve isoform selectivity. The results of these studies may guide the synthesis of more potent and selective HDAC inhibitors.
authors.affiliation: Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, United States.
authors.forename: Pravin
authors.initials: P
authors.lastname: Bhansali
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting/Blaustein Cancer Research Building 1, 1650 Orleans Street, Room 551, Baltimore, MD 21231, United States.
authors.forename: Christin L
authors.initials: CL
authors.lastname: Hanigan
authors.affiliation: Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, United States.
authors.forename: Lalith
authors.initials: L
authors.lastname: Perera
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting/Blaustein Cancer Research Building 1, 1650 Orleans Street, Room 551, Baltimore, MD 21231, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.affiliation: Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH 43606, United States. Electronic address: ltillek@utnet.utoledo.edu.
authors.forename: L M Viranga
authors.initials: LM
authors.lastname: Tillekeratne
mesh_terms: D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D013844:Thiazoles; C527895:largazole; D006655:Histone Deacetylases
keywords: Antiproliferation; Antitumor agents; Biological activity; Histone deacetylase inhibitors; Molecular modeling