Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5854-5865 |
| Number of pages | 12 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 15 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2007 |
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Keywords
- 3,5-Bis(arylidene)-4-piperidones
- Cytostatic activity
- Human N-myristoyltransferase
- Molecular modeling
- Murine toxicity
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
Cite this
E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones : A topographical study of some novel potent cytotoxins. / Jha, Amitabh; Mukherjee, Chandrani; Prasad, Ashok K.; Parmar, Virinder S.; Clercq, Erik De; Balzarini, Jan; Stables, James P.; Manavathu, Elias Kurian; Shrivastav, Anuraag; Sharma, Rajendra K.; Nienaber, Kurt H.; Zello, Gordon A.; Dimmock, Jonathan R.
In: Bioorganic and Medicinal Chemistry, Vol. 15, No. 17, 01.09.2007, p. 5854-5865.Research output: Contribution to journal › Article
}
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.
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
UR - http://www.scopus.com/inward/record.url?scp=34447329017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447329017&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2007.05.065
DO - 10.1016/j.bmc.2007.05.065
M3 - Article
VL - 15
SP - 5854
EP - 5865
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 17
ER -