title: Bis[3,5-bis(benzylidene)-4-oxo-1-piperidinyl]amides: a novel class of potent cytotoxins.
abstract: The principal objective of this study was the examination of the theory of cytotoxic synergism. In this exploratory study, we tested the hypothesis that doubling the number of sites available for thiol alkylation in a series of candidate cytotoxins increases potency more than two-fold. This concept was verified in one-third of our comparisons using human Molt 4/C8 and CEM T-lymphocytes and murine L1210 cells. In addition, the significant potencies of various members of our compound series justified further studies. Molecular modeling revealed that relative locations of the amidic groups correlate with cytotoxicity. A potent cytotoxic compound, 1,2-bis(3,5-dibenzylidene-4-oxo-piperidin-1-yl)ethane-1,2-dione (1a) inhibited the growth of a large number of human tumor cell lines and displayed greater toxicity toward certain non-adherent cells than toward adherent neoplasms or fibroblasts. The mode of action of 1a includes induction of apoptosis and necrosis.
authors.affiliation: Drug Design & Discovery Research Group, College of Pharmacy & Nutrition, University of Saskatchewan, 216 Thorvaldson, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
authors.forename: Swagatika
authors.initials: S
authors.lastname: Das
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramírez
authors.forename: Carolina
authors.initials: C
authors.lastname: Lema
authors.forename: Renato J
authors.initials: RJ
authors.lastname: Aguilera
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Dimmock
authors.forename: Dennis K J
authors.initials: DK
authors.lastname: Gorecki
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000478:Alkylation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: C569482:1,2-bis(3,5-dibenzylidene-4-oxopiperidin-1-yl)ethane-1,2-dione; D000577:Amides; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003603:Cytotoxins; D010881:Piperidones