title: Investigation of fatty acid conjugates of 3,5-bisarylmethylene-4-piperidone derivatives as antitumor agents and human topoisomerase-IIα inhibitors.
abstract: A series of five 3,5-bisarylidene-4-piperidones designed as analogs of curcumin and their twenty five fatty acid conjugates were synthesized as candidate anticancer agents. The fatty acid conjugates were designed for efficient delivery of these compounds at the targeted cancer sites. The cytostatic potential of these compounds was evaluated against three representative cancer cell lines namely murine leukemic L1210 cells, and human T-lymphocyte CEM cells and cervical HeLa cells. Most compounds were found to exhibit significant anti-cancer activity in vitro. QSAR studies indicated electrophilicity of these compounds towards cellular nucleophiles may have a key role to play in their cytostatic activity. Representative compounds were also tested for topoisomerase IIα inhibitory potential, which indicated strong catalytic inhibition of the enzyme in vitro. The data showed that the fatty acid conjugates also possessed robust antioxidant activity in multiple analyses. This study also indicated that these compounds prompted significantly lower cellular damage in human fibroblasts than a currently used cancer drug sorafenib in vitro. The wide spectrum of anticancer action, supplemented with antioxidant potential along with non-toxic manifestations, certainly augment the anticancer candidacy of the novel fatty acid conjugates.
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, Nova Scotia B4P 2R6, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Potter
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, Nova Scotia B4P 2R6, Canada.
authors.forename: Mamta
authors.initials: M
authors.lastname: Jha
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia B2N 5E3, Canada.
authors.forename: Khushwant S
authors.initials: KS
authors.lastname: Bhullar
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia B2N 5E3, Canada.
authors.forename: H P Vasantha
authors.initials: HP
authors.lastname: Rupasinghe
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, Nova Scotia B4P 2R6, Canada. Electronic address: ajha@acadiau.ca.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Jha
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D010881:Piperidones; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: 3,5-Bisarylmethylene-4-piperidones; Anti-oxidant; Curcumin analogs; Cytostatic activity; Fatty acid amides; Michael acceptor; QSAR; Topoisomerase IIα inhibitors