3,5-Bis(benzylidene)-4-oxo-1-phosphonopiperidines and Related Diethyl Esters: Potent Cytotoxins with Multi-Drug-Resistance Reverting Properties
| Autor: | Jan Balzarini, Dennis K.J. Gorecki, Erik De Clercq, Joseph Molnár, Ponniah Selvakumar, Swagatika Das, Umashankar Das, Rajendra K. Sharma, Brian Bandy, Jonathan R. Dimmock, Zoltán Baráth, Gabriele Schatte, Julianna Serly |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Cellular respiration Molecular Conformation Growth inhibitory Drug resistance Crystallography X-Ray Biochemistry Article Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery Animals Humans Cytotoxic T cell Structure–activity relationship General Pharmacology Toxicology and Pharmaceutics Leukemia L1210 Cytotoxicity Piperidones Pharmacology Cytotoxins Chemistry Organic Chemistry Drug Resistance Neoplasm Apoptosis Cell culture Molecular Medicine Drug Screening Assays Antitumor |
| Zdroj: | ChemMedChem. 4:1831-1840 |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.200900288 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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