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

Abstract

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