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Anilides and quinolones with nitrogen-bearing substituents from benzothiophene- and thienothiophene- series: synthesis, photochemical synthesis, cytostatic evaluation, 3D-derived QSAR analysis and DNA-binding properties

Aleksić, Maja; Bertoša, Branimir; Nhili, Raja; Depauw, Sabine; Martin-Kleiner, Irena; David-Cordonnier, Marie-Helene; Tomić, Sanja; Kralj, Marijeta; Karminski-Zamola, Grace (2014) Anilides and quinolones with nitrogen-bearing substituents from benzothiophene- and thienothiophene- series: synthesis, photochemical synthesis, cytostatic evaluation, 3D-derived QSAR analysis and DNA-binding properties. European Journal of Medicinal Chemistry, 71 . pp. 267-281. ISSN 0223-5234

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Abstract

A series of new anilides (2a-2c, 4, 5, 6, 7, 17a-c, 18) and quinolones (3a-b, 8a-b, 9a-b, 10, 11, 12, 13, 14, 15, 19) with nitrogen-bearing substituents from benzo[b]thiophene and thieno[2, 3-c]thiophene series are prepared. Benzo[b]thieno[2, 3-c]- and thieno[3′, 2′:4, 5]thieno[2, 3-c]quinolones (3a-b, 8a-b) are synthesized by the reaction of photochemical dehydrohalogenation from corresponding anilides. Anilides and quinolones were tested for the antiproliferative activity. Fused quinolones bearing protonated aminium group, quaternary ammonium group, N-methylated and protonated aminium group, amino and protonated amino group (8a, 9b, 10, 11, 12) showed very prominent anticancer activity, whereby the hydrochloride salt of N’, N’-dimethylamino-propyl-substituted quinolone (14) was the most active one, having the IC50 concentration at submicromolar range in accordance with previous QSAR predictions. On the other hand, flexible anilides were among the less active. Chemometric analysis of investigated compounds was performed. 3D-derived QSAR analysis identified solubility, metabolitic stability and the possibility of the compound to be ionised at pH 4-8 as molecular properties that are positively correlated with anticancer activity of investigated compounds, while molecular flexibility, polarizability and sum of hydrophobic surface areas were found to be negatively correlated. Anilides 2a-b, 4, 5, 6, 7 and quinolones 3a-b, 8a-b, 9b, 10, 11, 12, 13, 14 were evaluated for DNA binding propensities and topoisomerases I/II inhibition as part of their mechanism of action. Among the anilides, only compound 7 presented some DNA binding propensity. Quinolones 8b, 9b, 10, 11, 12, 13 and 14 bind to DNA as intercalators, whereas the strongest ones, the compounds 8b, 9b and 14, were by both, the PCA and PLS analysis clearly distinguished from the other compounds according to their molecular descriptors.

Item Type: Article
Additional Information: We greatly appreciate the financial support of the Croatian Ministry of Science Education and Sports (projects 125-0982464-1356, 098-098-1192344-2860, 098-098-2464-2514) and the bilateral Hubert Curien partnership between Croatian and French institutions (Cogito program) as the Egide project N24765PH. M.-H.D.-C. thanks the Association pour la Recherche sur le Cancer (ARC) Ligue Nationale Contre le Cancer (Comité du Pas-de-Calais, Septentrion), the Fonds Européen de Développement Régional (FEDER, European Community) and the Région Nord/Pas-de-Calais for grants (M-H.D.-C.), the Institut pour la Recherche sur le Cancer de Lille (IRCL) for Ph.D and post-doctoral fellowships (R.N.) and technicien expertise (S.D.).
Uncontrolled Keywords: amides, quinolones; antitumor evaluation; QSAR analysis; DNA-binding properties
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Molecular Medicine
Projects:
Project titleProject leaderProject codeProject type
Proučavanje biomakromolekula računalnim metodama i razvoj novih algoritama-Sanja Tomić098-1191344-2860MZOS
Novi heterocikli kao antitumorski i antivirusni (pametni) lijekovi-Marijana Hranjec125-0982464-1356MZOS
Uloga različitih mehanizama odgovora stanica na terapiju oštećenjem DNA-Marijeta Kralj098-0982464-2514MZOS
Depositing User: Irena Martin Kleiner
Date Deposited: 20 Dec 2016 11:51
Last Modified: 01 Feb 2017 14:27
URI: http://fulir.irb.hr/id/eprint/1972
DOI: 10.1016/j.ejmech.2013.11.010

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