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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-11, Vol.26 (23), p.7132
• Main Authors: Roayapalley, Praveen K, Dimmock, Jonathan R, Contreras, Lisett, Balderrama, Karol S, Aguilera, Renato J, Sakagami, Hiroshi, Amano, Shigeru, Sharma, Rajendra K, Das, Umashankar
• Format: Article
• Language: English
• Subjects: Ammonium; Ammonium salts; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cancer; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colorectal cancer; conjugated unsaturated ketones; Cytotoxicity; Cytotoxins; Fibroblasts; Humans; Laboratories; Leukemia; Membrane potential; Mitochondria; mitochondrial membrane potential; Nitrogen; Oximes; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; QSAR; Quantitative Structure-Activity Relationship; Quaternary Ammonium Compounds - chemical synthesis; Quaternary Ammonium Compounds - chemistry; Quaternary Ammonium Compounds - pharmacology; Quaternary ammonium salts; Salts; Selectivity; Toxicity; Tumors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26237132

A novel series of 1-[3-{3,5-bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone oximes - and related quaternary ammonium salts - were prepared as candidate antineoplastic agents. Evaluation against neoplastic Ca9-22, HSC-2 and HSC-4 cells revealed the compounds in series and to be potent cytotoxins with submicromolar CC 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, - are cytotoxic towards a number of leukemic and colon cancer cells. , lowered the mitochondrial membrane potential in CEM cells, and induced transient G2/M accumulation in Ca9-22 cells. Five compounds, namely , and , were identified as lead molecules that have drug-like properties.