title: 3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy.
abstract: A number of N-4-(2-aminoethoxy)phenylcarbonyl derivatives of various 3,5-bis(benzylidene)-4-piperidones 2-5 demonstrated noteworthy cytotoxic potencies towards human HL-60 leukemic cells as well as human HSC-2 and HSC-4 squamous cell carcinomas. In general, toxicity towards HGF, HPC, and HPLF normal cells was substantially lower. The highest selective toxicity was noted when the terminal base is morpholine. Lead optimization was based on finding compounds which had (i) high cytotoxic potencies, (ii) a greater toxicity to neoplasms than normal cells, and (iii) drug-likeness based on the rule of five. From the biodata generated, 5a evolved as a promising lead compound for further development. The mode of action of 5a included the induction of apoptosis in HL-60 cells in which internucleosomal DNA fragmentation and activation of caspase-3 was noted. In addition, 5a caused autophagy in HSC-2 cells.
authors.affiliation: Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5C9.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
authors.forename: Qing
authors.initials: Q
authors.lastname: Chu
authors.forename: Qintao
authors.initials: Q
authors.lastname: Wang
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Ponniah
authors.initials: P
authors.lastname: Selvakumar
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D010881:Piperidones / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: C526290:3,5-bis(benzylidene)-4-piperidone; D000970:Antineoplastic Agents; D003603:Cytotoxins; D010881:Piperidones