title: Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure.
abstract: Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA. chenx462@umn.edu
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.forename: Guangyao
authors.initials: G
authors.lastname: Gao
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Garrett T
authors.initials: GT
authors.lastname: McLean
authors.forename: Hiremagalur N
authors.initials: HN
authors.lastname: Jayaram
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C029010:cinnamic acid; D007168:IMP Dehydrogenase; D006655:Histone Deacetylases