title: Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: structure-activity relationships and potent antileukemic and antilymphoma cytotoxicity.
abstract: Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3-5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3-5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM. In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential.
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Yahaira
authors.initials: Y
authors.lastname: Santiago-Vazquez
authors.affiliation: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada.
authors.forename: Swagatika
authors.initials: S
authors.lastname: Das
authors.affiliation: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. Electronic address: umashankar.das@usask.ca.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Robles-Escajeda
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Ortega
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lema
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramírez
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA. Electronic address: raguilera@utep.edu.
authors.forename: Renato J
authors.initials: RJ
authors.lastname: Aguilera
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Department of Finance, Nanyang Technological University, Singapore 639798, Singapore.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Dimmock
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Dennis K J
authors.initials: DK
authors.lastname: Gorecki
authors.affiliation: Cytometry, Screening and Imaging Facility, Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008223:Lymphoma / Q000473:pathology*; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines
keywords: 4-Piperidone; Apoptosis; Cytotoxicity; Mitochondria; Structure–activity relationships; Unsaturated ketones