title: 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.
abstract: A series of new anilides (2a-c, 4-7, 17a-c, 18) and quinolones (3a-b, 8a-b, 9a-b, 10-15, 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, 10-12) showed very prominent anticancer activity, whereby the hydrochloride salt of N',N'-dimethylaminopropyl-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 ionized 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, 4-7 and quinolones 3a-b, 8a-b, 9b and 10-14 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 whereas the quinolones 8b, 9b and 10-14 intercalate in the DNA base pairs, compounds 8b, 9b and 14 being the most efficient ones. The strongest DNA intercalators, compounds 8b, 9b and 14, were clearly distinguished from the other compounds according to their molecular descriptors by the PCA and PLS analysis.
authors: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
authors: Maja
authors: M
authors: Aleksić
authors: Division of Physical Chemistry, "Ruđer Bošković" Institute, Bijenička Cesta 54, P.O. Box 1016, HR-10000 Zagreb, Croatia; Division of Physical Chemistry, Faculty of Natural Sciences, University of Zagreb, Horvatovac 102A, HR-10000 Zagreb, Croatia. Electronic address: bbertosa@irb.hr.
authors: Branimir
authors: B
authors: Bertoša
authors: INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille Nord de France, IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille Cedex, France.
authors: Raja
authors: R
authors: Nhili
authors: INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille Nord de France, IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille Cedex, France.
authors: Sabine
authors: S
authors: Depauw
authors: Division of Molecular Medicine, "Ruđer Bošković" Institute, Bijenička Cesta 54, P.O. Box 1016, HR-10000 Zagreb, Croatia.
authors: Irena
authors: I
authors: Martin-Kleiner
authors: INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille Nord de France, IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille Cedex, France.
authors: Marie-Hélène
authors: MH
authors: David-Cordonnier
authors: Division of Physical Chemistry, "Ruđer Bošković" Institute, Bijenička Cesta 54, P.O. Box 1016, HR-10000 Zagreb, Croatia.
authors: Sanja
authors: S
authors: Tomić
authors: Division of Molecular Medicine, "Ruđer Bošković" Institute, Bijenička Cesta 54, P.O. Box 1016, HR-10000 Zagreb, Croatia.
authors: Marijeta
authors: M
authors: Kralj
authors: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia. Electronic address: gzamola@fkit.hr.
authors: Grace
authors: G
authors: Karminski-Zamola
mesh_terms: D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009584:Nitrogen / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D015363:Quinolones; D013876:Thiophenes; D059005:Topoisomerase II Inhibitors; C088015:benzothiophene; D004247:DNA; D009584:Nitrogen
keywords: Amides; Antitumor evaluation; DNA-binding properties; QSAR analysis; Quinolones