N–Acyl–3,5–bis(arylidene)-4-piperidones and related compounds which stimulate fyn kinase

Abstract

This study is part of a long term project designed to explore the hypothesis that stimulation of cancer cells followed by treatment with one or more cytotoxic agents may create greater damage to tumours than to the corresponding normal tissues. The aim of the present investigation was to discover various compounds which stimulate a protein tyrosine kinase, namely fyn kinase. The N-acyl-3,5-bis(arylidene)-4-piperidones and related analogues activated this enzyme using concentrations of 25 μM while representative molecules achieved this result at 0.1 μM. Molecular modelling suggested that the compounds interact transiently with the ATP binding site of fyn kinase thereby enhancing the catalytic phosphorylation of proteins. In the future, candidate antineoplastic agents will be designed which incorporate the structural features of these enzyme stimulators with the goal of their being formed in vitro and in vivo prior to the release of cytotoxins.

Keywords::

• Enzyme stimulation
• fyn kinase
• molecular modelling
• 4-piperidones

Acknowledgements

The authors thank the Canadian Institutes of Health Research for operating grants to R. K. Sharma and J. R. Dimmock while appreciation is extended to the Canadian Foundation for Innovation who awarded a grant to T. A. Haas. Ms B. McCullough is thanked for typing various drafts of this paper.