3,5‐Bis(benzylidene)‐4‐oxo‐1‐phosphonopiperidines and Related Diethyl Esters: Potent Cytotoxins with Multi‐Drug‐Resistance Reverting Properties |
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Authors: | Swagatika Das Umashankar Das Dr Ponniah Selvakumar Dr Rajendra?K Sharma Dr Jan Balzarini Prof?Dr Erik De?Clercq Prof?Dr Joseph Molnár Prof?Dr Julianna Serly Zoltán Baráth Dr Gabriele Schatte Dr Brian Bandy Dr Dennis K?J Gorecki Prof?Dr Jonathan?R Dimmock Prof?Dr |
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Affiliation: | 1. Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N?5C9 (Canada), Fax: (+1)?306‐966‐6377;2. ;3. Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N?4H4 (Canada);4. Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven (Belgium);5. Institute of Medical Microbiology and Immunology, University of Szeged, Szeged 6720 (Hungary);6. Saskatchewan Structural Sciences Centre, University of Saskatchewan, Saskatoon, SK S7N?5C9 (Canada) |
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Abstract: | A series of 3,5‐bis(benzylidene)‐4‐piperidones 3 were converted into the corresponding 3,5‐bis(benzylidene)‐1‐phosphono‐4‐piperidones 5 via diethyl esters 4 . The analogues in series 4 and 5 displayed marked growth inhibitory properties toward human Molt 4/C8 and CEM T‐lymphocytes as well as murine leukemia L1210 cells. In general, the N‐phosphono compounds 5 , which are more hydrophilic than the analogues in series 3 and 4 , were the most potent cluster of cytotoxins, and, in particular, 3,5‐bis‐(2‐nitrobenzylidene)‐1‐phosphono‐4‐piperidone 5 g had an average IC50 value of 34 nM toward the two T‐lymphocyte cell lines. Four of the compounds displayed potent cytotoxicity toward a panel of nearly 60 human tumor cell lines, and nanomolar IC50 values were observed in a number of cases. The mode of action of 5 g includes the induction of apoptosis and inhibition of cellular respiration. Most of the members of series 4 as well as several analogues in series 5 are potent multi‐drug resistance (MDR) reverting compounds. Various correlations were noted between certain molecular features of series 4 and 5 and cytotoxic properties, affording some guidelines in expanding this study. |
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Keywords: | 4‐piperidones cytotoxicity multi‐drug resistance phosphono derivatives unsaturated ketones |
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