title: Novel derivatives of pyridylbenzo[b]thiophene-2-carboxamides and benzo[b]thieno[2,3-c]naphthyridin-2-ones: minor structural variations provoke major differences of antitumor action mechanisms.
abstract: Novel cyano- and 2-imidazolinyl-substituted derivatives of pyridylbenzo[b]thiophene-2-carboxamides 4, 5, 10-13 and benzo[b]thieno[2,3-c]naphthyridin-2-ones 6, 7, 14-17 were prepared. All derivatives showed a prominent antiproliferative effect. Extensive DNA binding studies and additional biological evaluations point to various modes/targets of action. The results strongly support intercalation into DNA as a dominant binding mode of fused analogues, which was substantiated using topoisomerase I inhibition assay. Most intriguingly, only minor structural difference between "nonfused" compounds 12 and 13 has strong impact on the interactions with DNA; while 13 binds within the DNA minor groove in the form of dimer, 12 does not form significant interactions with DNA. The assumption that severe mitotic impairment (G2/M phase arrest) induced by 12 could point to tubulin, another important target, was confirmed by its obvious anti-tubulin activity observed in immunofluorescence assay, whereby treated cells showed disruption of microtubule formation comparable to the effect obtained by paclitaxel, a well-known tubulin antagonist chemotherapeutic.
authors.affiliation: Division of Molecular Medicine, "Ruder Boskovic" Institute, Bijenicka Cesta 54, P.O. Box 180, HR-10000 Zagreb, Croatia.
authors.forename: Katja
authors.initials: K
authors.lastname: Ester
authors.forename: Marijana
authors.initials: M
authors.lastname: Hranjec
authors.forename: Ivo
authors.initials: I
authors.lastname: Piantanida
authors.forename: Irena
authors.initials: I
authors.lastname: Caleta
authors.forename: Ivana
authors.initials: I
authors.lastname: Jarak
authors.forename: Kresimir
authors.initials: K
authors.lastname: Pavelić
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola