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Design, Synthesis and Evaluation of Novel 1-(Substituted Acetyl)-4-(10-Bromo-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-B]Pyridine-11-Ylidene)piperidines as Antitumor Agents and Farnesyl Protein Transferase Inhibitors.

Gatne PS, Viswanathan CL, Ambre PK, Juvekar A - Indian J Pharm Sci (2010)

Bottom Line: Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin.Compound 6e was most active with IC(50) values of <15 μM in two cell lines tested.Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 μM.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz, Mumbai-400 098, India.

ABSTRACT
Eight novel 1-(substituted acetyl)-4-(10-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta [1,2-b] pyridine-11-ylidene)piperidines were designed by incorporating zinc binding groups to enhance activity. The designed molecules were synthesized and were evaluated for antitumor activity in vitro in five cell lines and for farnesyl protein transferase inhibition. Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin. Compound 6e was most active with IC(50) values of <15 μM in two cell lines tested. Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 μM.

No MeSH data available.


Flexible alignment of lonafarnib with compound I and test compounds (6e). Alignment of I with lonafarnib (2a) and with one of the test compounds (6e) is given in fi g. 2b. From 2b, it is clear that alignment of 6e is highly signifi cant compared to that of lonafarnib
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Figure 2: Flexible alignment of lonafarnib with compound I and test compounds (6e). Alignment of I with lonafarnib (2a) and with one of the test compounds (6e) is given in fi g. 2b. From 2b, it is clear that alignment of 6e is highly signifi cant compared to that of lonafarnib

Mentions: Conformers of I, lonafarnib® and test molecules (6a--h) (general structure II) were generated by using dynamic simulations at the temperature of 310° and the sampling time was 5×10-4 s and the lowest energy conformations were identified for each molecule. Keeping I as template, lonafarnib and 6a-h were superimposed with similarity terms being Aromaticity, Hydrophobe, LogP (o/w) and Hydrogen bond acceptor. Similarity index (F); Average strain energy (U) and Alignment score (S) were measured and are given in Table 1. Lower scores indicate greater similarity and better alignment. Alignment of I with lonafarnib (fig. 2a) and with one of the test compounds (6e) is given in fig. 2b. From fig. 2b, it is clear that alignment of 6e is highly significant compared to that of lonafarnib.


Design, Synthesis and Evaluation of Novel 1-(Substituted Acetyl)-4-(10-Bromo-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-B]Pyridine-11-Ylidene)piperidines as Antitumor Agents and Farnesyl Protein Transferase Inhibitors.

Gatne PS, Viswanathan CL, Ambre PK, Juvekar A - Indian J Pharm Sci (2010)

Flexible alignment of lonafarnib with compound I and test compounds (6e). Alignment of I with lonafarnib (2a) and with one of the test compounds (6e) is given in fi g. 2b. From 2b, it is clear that alignment of 6e is highly signifi cant compared to that of lonafarnib
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116320&req=5

Figure 2: Flexible alignment of lonafarnib with compound I and test compounds (6e). Alignment of I with lonafarnib (2a) and with one of the test compounds (6e) is given in fi g. 2b. From 2b, it is clear that alignment of 6e is highly signifi cant compared to that of lonafarnib
Mentions: Conformers of I, lonafarnib® and test molecules (6a--h) (general structure II) were generated by using dynamic simulations at the temperature of 310° and the sampling time was 5×10-4 s and the lowest energy conformations were identified for each molecule. Keeping I as template, lonafarnib and 6a-h were superimposed with similarity terms being Aromaticity, Hydrophobe, LogP (o/w) and Hydrogen bond acceptor. Similarity index (F); Average strain energy (U) and Alignment score (S) were measured and are given in Table 1. Lower scores indicate greater similarity and better alignment. Alignment of I with lonafarnib (fig. 2a) and with one of the test compounds (6e) is given in fig. 2b. From fig. 2b, it is clear that alignment of 6e is highly significant compared to that of lonafarnib.

Bottom Line: Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin.Compound 6e was most active with IC(50) values of <15 μM in two cell lines tested.Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 μM.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz, Mumbai-400 098, India.

ABSTRACT
Eight novel 1-(substituted acetyl)-4-(10-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta [1,2-b] pyridine-11-ylidene)piperidines were designed by incorporating zinc binding groups to enhance activity. The designed molecules were synthesized and were evaluated for antitumor activity in vitro in five cell lines and for farnesyl protein transferase inhibition. Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin. Compound 6e was most active with IC(50) values of <15 μM in two cell lines tested. Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 μM.

No MeSH data available.