TY - JOUR
T1 - E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones
T2 - A topographical study of some novel potent cytotoxins
AU - Jha, Amitabh
AU - Mukherjee, Chandrani
AU - Prasad, Ashok K.
AU - Parmar, Virinder S.
AU - Clercq, Erik De
AU - Balzarini, Jan
AU - Stables, James P.
AU - Manavathu, Elias Kurian
AU - Shrivastav, Anuraag
AU - Sharma, Rajendra K.
AU - Nienaber, Kurt H.
AU - Zello, Gordon A.
AU - Dimmock, Jonathan R.
N1 - Funding Information:
The authors thank the following agencies for financial support, namely the Nova Scotia Health Research Foundation (A.J.), Canadian Institutes of Health Research (A.J., J.R.D., R.K.S), Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (J. B., E.D.C.), and the Department of Biotechnology, DBT, New Delhi (A. K P. and V.S.P.). Appreciation is extended to Mrs. Lizette van Berckelaer for conducting the Molt 4/C8, CEM, and L1210 assays, the National Cancer Institute, USA, which provided the data using the panel of human tumor cell lines and the National Institute of Neurological Disorders and Stroke, USA for undertaking the short-term toxicity studies in mice.
PY - 2007/9/1
Y1 - 2007/9/1
N2 - A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC50 figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 μM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.
AB - A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC50 figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 μM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.
KW - 3,5-Bis(arylidene)-4-piperidones
KW - Cytostatic activity
KW - Human N-myristoyltransferase
KW - Molecular modeling
KW - Murine toxicity
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U2 - 10.1016/j.bmc.2007.05.065
DO - 10.1016/j.bmc.2007.05.065
M3 - Article
C2 - 17562365
AN - SCOPUS:34447329017
SN - 0968-0896
VL - 15
SP - 5854
EP - 5865
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 17
ER -