title: Tropolones as lead-like natural products: the development of potent and selective histone deacetylase inhibitors.
abstract: Natural products have long been recognized as a rich source of potent therapeutics but further development is often limited by high structural complexity and high molecular weight. In contrast, at the core of the thujaplicins is a lead-like tropolone scaffold characterized by relatively low molecular weight, ample sites for diversification, and metal-binding functionality poised for targeting a range of metalloenzyme drug targets. Here, we describe the development of this underutilized scaffold for the discovery of tropolone derivatives that function as isozyme-selective inhibitors of the validated anticancer drug target, histone deacetylase (HDAC). Several monosubstituted tropolones display remarkable levels of selectivity for HDAC2 and potently inhibit the growth of T-cell lymphocyte cell lines. The tropolones represent a new chemotype of isozyme-selective HDAC inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Ononye
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: VanHeyst
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: E Zachary
authors.initials: EZ
authors.lastname: Oblak
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: Wangda
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ammar
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Anderson
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06269, United States.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
keywords: HDAC; T-lymphocyte cancer cell lines; Tropolone; isozyme-selectivity; metalloenzyme; thujaplicin