title: Curcumin-inspired cytotoxic 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones: A novel group of topoisomerase II alpha inhibitors.
abstract: Three series of novel 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones, designed as simplified analogs of curcumin with maleic diamide tether, were synthesized and bioevaluated. These compounds displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemic cells. In contrast, the related N-arylmaleamic acids possessed little or no cytotoxicity in these three screens. Design of these compounds was based on molecular modeling studies performed on a related series of molecule in a previous study. Representative title compounds were found to be significantly potent in inhibiting the activity of topoisomerase II alpha indicating the possible mode of action of these compounds. These compounds were also potent antioxidants in vitro and attenuated the AAPH triggered peroxyl radical production in human fibroblasts. Various members of these series were also well tolerated in both in vitro and in vivo toxicity analysis.
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS, Canada. Electronic address: ajha@acadiau.ca.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Jha
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS, Canada.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Duffield
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS, Canada.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ness
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS, Canada.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Ravoori
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Andrews
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS, Canada.
authors.forename: Khushwant S
authors.initials: KS
authors.lastname: Bhullar
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS, Canada.
authors.forename: H P Vasantha
authors.initials: HP
authors.lastname: Rupasinghe
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D010881:Piperidones / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D017382:Reactive Oxygen Species / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D010881:Piperidones; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; D003474:Curcumin
keywords: 4-Piperidones; Curcumin analogs; Cytostatic activity; Maleamic acids; QSAR; Topoisomerase IIα inhibition