3,5-Bis(benzylidene)-4-oxo-1-phosphonopiperidines and Related Diethyl Esters: Potent Cytotoxins with Multi-Drug-Resistance Reverting Properties
✍ Scribed by Swagatika Das; Umashankar Das; Ponniah Selvakumar; Rajendra K. Sharma; Jan Balzarini; Erik De Clercq; Joseph Molnár; Julianna Serly; Zoltán Baráth; Gabriele Schatte; Brian Bandy; Dennis K. J. Gorecki; Jonathan R. Dimmock
- Book ID
- 102105000
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 296 KB
- Volume
- 4
- Category
- Article
- ISSN
- 1860-7179
No coin nor oath required. For personal study only.
✦ Synopsis
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 IC~50~ 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 IC~50~ 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.__