title: Design and synthesis of novel pyrimidine hydroxamic acid inhibitors of histone deacetylases.
abstract: Inhibition of histone deacetylase activity represents a promising new modality in the treatment of a number of cancers. A novel HDAC series demonstrating inhibitory activity in cell proliferation assays is described. Optimisation based on the introduction of basic amine linkers to effect good drug distribution to tumour led to the identification of a compound with oral activity in a human colon cancer xenograft study associated with increased histone H3 acetylation in tumour tissue.
authors.affiliation: Chroma Therapeutics, 93 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. adonald@chromatherapeutics.com
authors.forename: Alastair D G
authors.initials: AD
authors.lastname: Donald
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Clark
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Day
authors.forename: Martin G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: Judata
authors.initials: J
authors.lastname: Wibata
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stimson
authors.forename: Anthea
authors.initials: A
authors.lastname: Hardcastle
authors.forename: Sue A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Deborah
authors.initials: D
authors.lastname: McNamara
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Needham
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
authors.forename: David F
authors.initials: DF
authors.lastname: Moffat
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry*; D014183:Transplantation, Heterologous
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011743:Pyrimidines; C030986:pyrimidine