Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 11, Pages 5044-5060Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm300505h
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Funding
- Croatian Ministry of Science Education and Sports [125-0982464-1356, 098-1191344-2860, 098-0982464-2514]
- bilateral Hubert Curien partnership [24765PH]
- Association Laurette Fugain
- Ligue Nationale Contre le Cancer (Comite du Pas-de Calais, Septentrion)
- European Community
- Region Nord-Pas de Calais
- Universite de Lille-2
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A series of new N,N-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo[b]thienyl- and thieno[2,3-b]thienylcarboxanilides and benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity. 2-Imidazolinyl-substituted derivatives showed very prominent activity. By use of the experimentally obtained antitumor measurements, 3D-derived QSAR analysis was performed for the set of compounds. Higly predicitive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides 6a-c and quinolones 9a-c and 11a were evaluated for DNA binding propensities and topoisomerases I and II inhibition as part of their mechanism of action assessment. The evaluated differences in the mode of action nicely correlate with the results of the 3D-QSAR analysis. Taken together, the results indicate which modifications of the compounds from the series should further improve their anticancer properties.
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