Design, Synthesis and Tumour-Selective Toxicity of Novel 1-[3-{3,5-Bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone Oximes and Related Quaternary Ammonium Salts
Praveen K. Roayapalley,
Jonathan R. Dimmock,
Lisett Contreras,
Karol S. Balderrama,
Renato J. Aguilera,
Hiroshi Sakagami,
Shigeru Amano,
Rajendra K. Sharma,
Umashankar Das
Affiliations
Praveen K. Roayapalley
Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Jonathan R. Dimmock
Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Lisett Contreras
Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA
Karol S. Balderrama
Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA
Renato J. Aguilera
Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA
Hiroshi Sakagami
Research Institute of Odontology, Meikai University, Sakado, Saitama 350-0283, Japan
Shigeru Amano
Research Institute of Odontology, Meikai University, Sakado, Saitama 350-0283, Japan
Rajendra K. Sharma
Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Umashankar Das
Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
A novel series of 1-[3-{3,5-bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone oximes 3a–h and related quaternary ammonium salts 4a–h were prepared as candidate antineoplastic agents. Evaluation against neoplastic Ca9-22, HSC-2 and HSC-4 cells revealed the compounds in series 3 and 4 to be potent cytotoxins with submicromolar CC50 values in virtually all cases. In contrast, the compounds were less cytocidal towards HGF, HPLF and HPC non-malignant cells revealing their tumour-selective toxicity. Quantitative structure–activity relationships revealed that, in general, both cytotoxic potency and selectivity index figures increased as the magnitude of the Hammett sigma values rose. In addition, 3a–h are cytotoxic towards a number of leukemic and colon cancer cells. 4b,c lowered the mitochondrial membrane potential in CEM cells, and 4d induced transient G2/M accumulation in Ca9-22 cells. Five compounds, namely 3c,d and 4c–e, were identified as lead molecules that have drug-like properties.
