3,5-bis(benzylidene)-4-oxo-1-phosphonopiperidines and related diethyl esters: Potent cytotoxins with multi-drug-resistance reverting properties

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

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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 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.

Original languageEnglish
Pages (from-to)1831-1840
Number of pages10
JournalChemMedChem
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 2 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Das, S., Das, U., Selvakumar, P., Sharma, R. K., Balzarini, J., De Clercq, E., Molnár, J., Serly, J., Baráth, Z., Schatte, G., Bandy, B., Gorecki, D. K. J., & Dimmock, J. R. (2009). 3,5-bis(benzylidene)-4-oxo-1-phosphonopiperidines and related diethyl esters: Potent cytotoxins with multi-drug-resistance reverting properties. ChemMedChem, 4(11), 1831-1840. https://doi.org/10.1002/cmdc.200900288