Naslov
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

Autori
Ester, Katja ; Hranjec, Marijana ; Piantanida, Ivo ; Ćaleta, Irena ; Ivana, Jarak ; Pavelić, Krešimir ; Kralj, Marijeta ; Karminski-Zamola, Grace

Izvornik
Journal of medicinal chemistry (0022-2623) 52 (2009), 8; 2482-2492

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
pyridyl-benzo[b]thiophene-2-carboxamides and benzo[b]thieno[2 ; 3-c]naphthyridin-2-ones ; DNA binding ; anticancer activity ; topoisomerase I inhibition ; anti-tubulin activity ; intercalators ; minor groove
(pyridyl-benzo[b] thiophene-2-carboxamides and benzo[b]thieno[2 ; 3-c]naphthyridin-2-ones ; DNA binding ; anticancer activity ; topoisomerase I inhibition ; anti-tubulin activity ; intercalators ; minor groove)

Sažetak
Novel cyano- and 2-imidazolinyl-substituted derivatives of pyridyl-benzo[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 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 non-fused 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 another important target-tubulin 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, well-known tubulin antagonist chemotherapeutic.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA