期刊
CHEMMEDCHEM
卷 4, 期 11, 页码 1831-1840出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.200900288
关键词
4-piperidones; cytotoxicity; multi-drug resistance; phosphono derivatives; unsaturated ketones
资金
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council
- Belgian Fonds voor Wetenschappelijk Onderzoek (Vlaanderen)
- Szeged Foundation of Cancer Research (Hungary)
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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