title: 6-Benzylidene-2-[4-(pyridin-3-ylcarboxy)benzylidene]cyclohexanones: A novel cluster of tumour-selective cytotoxins.
abstract: Novel cytotoxins 3-5 containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are disclosed. The compounds in series 3 and 5 have the potential to liberate niacin which may reduce some of the side effects of antineoplastic compounds. 3a-c emerged as the most potent cytotoxic compounds with IC50values in the low micromolar range against human Molt4/C8 and CEM CD4+T-lymphocytes as well as murine L1210 leukemia cells. QSAR studies revealed that cytotoxic potencies were negatively correlated with the magnitude of the Hammett sigma values of the aryl substituents. The compounds 3a-e displayed tumour-selective toxicity against human HL-60, HSC-2, HSC-3 and HSC-4 neoplasms as compared to human HGF, HPC and HPLF nonmalignant cells. A representative potent compound 3a caused PARP1 cleavage and G0/G1cell cycle arrest in HSC-2 cells. These compounds are well tolerated in mice at doses up to and including 300mg/kg of the compounds and no mortalities were noted after 4h. The stability studies undertaken did not reveal that a representative compound 3a underwent hydrolysis to the related phenol 2a. Some guidelines for further analog development of the novel esters 3 were made.
authors.affiliation: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Atulya K
authors.initials: AK
authors.lastname: Panda
authors.affiliation: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada. Electronic address: umashankar.das@usask.ca.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.affiliation: Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Umemura
authors.affiliation: Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
authors.affiliation: Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.affiliation: Rega Institute of Medical Research, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Rega Institute of Medical Research, KU Leuven, 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: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Roayapalley
authors.affiliation: Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada. Electronic address: jr.dimmock@usask.ca.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001597:Benzylidene Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009525:Niacin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: C000621535:4-((3-benzylidene-2-oxocyclohexylidene)methyl)phenyl nicotinate; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003512:Cyclohexanones; D009525:Niacin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D008558:Melphalan
keywords: Conjugated unsaturated ketones; Cytotoxins; Niacin; QSAR; Structure-activity relationships; Tumour-selective toxicity