Design and synthesis of novel pyrimidine hydroxamic acid inhibitors of histone deacetylases.
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.
Donald
Alastair D G
AD
Chroma Therapeutics, 93 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. adonald@chromatherapeutics.com
Clark
Vanessa L
VL
Patel
Sanjay
S
Day
Francesca A
FA
Rowlands
Martin G
MG
Wibata
Judata
J
Stimson
Lindsay
L
Hardcastle
Anthea
A
Eccles
Sue A
SA
McNamara
Deborah
D
Needham
Lindsey A
LA
Raynaud
Florence I
FI
Aherne
Wynne
W
Moffat
David F
DF
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
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011743:Pyrimidines; C030986:pyrimidine