title: Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth.
abstract: The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Bergman
authors.forename: Karrune
authors.initials: K
authors.lastname: Woan
authors.forename: Patricio
authors.initials: P
authors.lastname: Perez-Villarroel
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villagra
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Sotomayor
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D007527:Isoenzymes; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014508:Urea / Q000737:chemistry*
chemical_list: C577944:4-((1-butyl-3-phenylureido)methyl)-N-hydroxybenzamide; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007527:Isoenzymes; D010671:Phenylurea Compounds; D014508:Urea; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases