title: Histone-deacetylase-targeted fluorescent ruthenium(II) polypyridyl complexes as potent anticancer agents.
abstract: Histone deacetylases inhibitors (HDACis) have gained much attention as a new class of anticancer agents in recent years. Herein, we report a series of fluorescent ruthenium(II) complexes containing N(1)-hydroxy-N(8)-(1,10-phenanthrolin-5-yl)octanediamide (L), a suberoylanilide hydroxamic acid (SAHA) derivative, as a ligand. As expected, these complexes show interesting chemiphysical properties, including relatively high quantum yields, large Stokes shifts, and long emission lifetimes. The in vitro inhibitory effect of the most effective drug, [Ru(DIP)2L](PF6)2 (3; DIP: 4,7-diphenyl-1,10-phenanthroline), on histone deacetylases (HDACs) is approximately equivalent in activity to that of SAHA, and treatment with complex 3 results in increased levels of the acetylated histone H3. Complex 3 is highly active against a panel of human cancer cell lines, whereas it shows relatively much lower toxicity to normal cells. Further mechanism studies show that complex 3 can elicit cell cycle arrest and induce apoptosis through mitochondria-related pathways and the production of reactive oxygen species. These data suggest that these fluorescent ruthenium(II)-HDACi conjugates may represent a promising class of anticancer agents for potential dual imaging and therapeutic applications targeting HDACs.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China.
authors.forename: Rui-Rong
authors.initials: RR
authors.lastname: Ye
authors.forename: Zhuo-Feng
authors.initials: ZF
authors.lastname: Ke
authors.forename: Cai-Ping
authors.initials: CP
authors.lastname: Tan
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Ji
authors.forename: Zong-Wan
authors.initials: ZW
authors.lastname: Mao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000032:analysis; D012428:Ruthenium / Q000737:chemistry*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008024:Ligands; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D000077337:Vorinostat; D012428:Ruthenium; D006655:Histone Deacetylases
keywords: antitumor agents; apoptosis; enzymes; inhibitors; ruthenium