title: Thiol-Based Potent and Selective HDAC6 Inhibitors Promote Tubulin Acetylation and T-Regulatory Cell Suppressive Function.
abstract: Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Mariana C F
authors.initials: MC
authors.lastname: Segretti
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Vallerini
authors.affiliation: Burke-Cornell Medical Research Institute , White Plains, New York 10605, United States ; Department of Neurology and Neuroscience, Weill Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Camille
authors.initials: C
authors.lastname: Brochier
authors.affiliation: Burke-Cornell Medical Research Institute , White Plains, New York 10605, United States ; Department of Neurology and Neuroscience, Weill Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Brett
authors.initials: B
authors.lastname: Langley
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
keywords: 1,2,3,4-tetrahydroquinoline; 8-aminoquinoline; HDAC6-selective inhibitors; Treg; mercaptoacetamides