title: Evaluation of class I HDAC isoform selectivity of largazole analogues.
abstract: Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors.
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States.
authors: Bumki
authors: B
authors: Kim
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States.
authors: Heekwang
authors: H
authors: Park
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States; Marine Science Institute, College of Science, University of the Philippines, Diliman, Quezon City 1100, Philippines.
authors: Lilibeth A
authors: LA
authors: Salvador
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States.
authors: Patrick E
authors: PE
authors: Serrano
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States.
authors: Jason C
authors: JC
authors: Kwan
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States.
authors: Sabrina L
authors: SL
authors: Zeller
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL 32610, United States.
authors: Qi-Yin
authors: QY
authors: Chen
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States.
authors: Soyoung
authors: S
authors: Ryu
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL 32610, United States.
authors: Yanxia
authors: Y
authors: Liu
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States.
authors: Seongrim
authors: S
authors: Byeon
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL 32610, United States. Electronic address: luesch@cop.ufl.edu.
authors: Hendrik
authors: H
authors: Luesch
authors: Department of Chemistry, Duke University, Durham, NC 27708, United States; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: jiyong.hong@duke.edu.
authors: Jiyong
authors: J
authors: Hong
mesh_terms: D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D013844:Thiazoles; C527895:largazole; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: Class I histone deacetylase; HDAC inhibitor; Isoform selectivity; Largazole; Structure–activity relationship