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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.


Synthesis of test compounds 6a-h Reagents and conditions (a) concentrated H2SO4, KNO3, -5°, 30 min; (b) SnCl2.2H2O, RT, 1 h; (c) Br2, AcOH, 15°, 2 h; (d) i) NaNO2, concentrated HCl, 0°, 1 h ii) hypophosphorus acid, 5°, 2 h
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Figure 3: Synthesis of test compounds 6a-h Reagents and conditions (a) concentrated H2SO4, KNO3, -5°, 30 min; (b) SnCl2.2H2O, RT, 1 h; (c) Br2, AcOH, 15°, 2 h; (d) i) NaNO2, concentrated HCl, 0°, 1 h ii) hypophosphorus acid, 5°, 2 h

Mentions: 10-Bromodesloratadine (3) was prepared from loratadine (1) by nitration using conc. sulfuric acid and potassium nitrate at -10° for 30 min to get a mixture of two nitro isomers (9-nitro- and 7-nitro-loratadine). The nitro group in the mixed isomers was then reduced to amine using stannous chloride dihydrate in ethyl acetate at room temperature. The mixed amines formed were then brominated using bromine in acetic acid at 15-20° to achieve bromination at the C10 position on ring. Diazotization of amine function with sodium nitrite and concentrated HCl at 0° followed by treatment with hypophosphorous acid at 5° gave 10-bromoloratadine (2) as a single isomer. 10-bromoloratadine was decarboethoxylated using sodium hydroxide in methanol at reflux to get 10-bromodesloratadine. Further reaction with chloroacetyl chloride gave an intermediate (4), which was then condensed with various substituted amines or thiols (5a-h) in dimethyl formamide (DMF) in presence of base like potassium carbonate or sodium hydride to get test compounds 6a-h (Scheme 1).


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)

Synthesis of test compounds 6a-h Reagents and conditions (a) concentrated H2SO4, KNO3, -5°, 30 min; (b) SnCl2.2H2O, RT, 1 h; (c) Br2, AcOH, 15°, 2 h; (d) i) NaNO2, concentrated HCl, 0°, 1 h ii) hypophosphorus acid, 5°, 2 h
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Synthesis of test compounds 6a-h Reagents and conditions (a) concentrated H2SO4, KNO3, -5°, 30 min; (b) SnCl2.2H2O, RT, 1 h; (c) Br2, AcOH, 15°, 2 h; (d) i) NaNO2, concentrated HCl, 0°, 1 h ii) hypophosphorus acid, 5°, 2 h
Mentions: 10-Bromodesloratadine (3) was prepared from loratadine (1) by nitration using conc. sulfuric acid and potassium nitrate at -10° for 30 min to get a mixture of two nitro isomers (9-nitro- and 7-nitro-loratadine). The nitro group in the mixed isomers was then reduced to amine using stannous chloride dihydrate in ethyl acetate at room temperature. The mixed amines formed were then brominated using bromine in acetic acid at 15-20° to achieve bromination at the C10 position on ring. Diazotization of amine function with sodium nitrite and concentrated HCl at 0° followed by treatment with hypophosphorous acid at 5° gave 10-bromoloratadine (2) as a single isomer. 10-bromoloratadine was decarboethoxylated using sodium hydroxide in methanol at reflux to get 10-bromodesloratadine. Further reaction with chloroacetyl chloride gave an intermediate (4), which was then condensed with various substituted amines or thiols (5a-h) in dimethyl formamide (DMF) in presence of base like potassium carbonate or sodium hydride to get test compounds 6a-h (Scheme 1).

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.