3,5-Bis(benzylidene)-4-oxo-1-phosphonopiperidines and related diethyl esters: Potent cytotoxins with multi-drug-resistance reverting properties.
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.
University of Saskatchewan, Saskatoon, Canada.
Swagatika
S
Das
Umashankar
U
Das
Ponniah
P
Selvakumar
Rajendra K
RK
Sharma
Jan
J
Balzarini
Erik
E
De Clercq
Joseph
J
Molnár
Julianna
J
Serly
Zoltán
Z
Baráth
Gabriele
G
Schatte
Brian
B
Bandy
Dennis K J
DK
Gorecki
Jonathan R
JR
Dimmock
D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship
D003603:Cytotoxins; D010881:Piperidones