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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Cell Cycle / drug effects
-
Cell Line, Tumor
-
DNA / chemistry
-
DNA Topoisomerases, Type I / chemistry
-
Dimerization
-
Drug Screening Assays, Antitumor
-
Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
-
Heterocyclic Compounds, 4 or More Rings / chemistry
-
Heterocyclic Compounds, 4 or More Rings / pharmacology
-
Humans
-
Intercalating Agents / chemical synthesis
-
Intercalating Agents / chemistry
-
Intercalating Agents / pharmacology
-
Naphthyridines / chemical synthesis*
-
Naphthyridines / chemistry
-
Naphthyridines / pharmacology
-
Nucleic Acid Denaturation
-
Structure-Activity Relationship
-
Thiophenes / chemical synthesis*
-
Thiophenes / chemistry
-
Thiophenes / pharmacology
-
Topoisomerase I Inhibitors
-
Tubulin Modulators / chemical synthesis
-
Tubulin Modulators / chemistry
-
Tubulin Modulators / pharmacology
Substances
-
Antineoplastic Agents
-
Heterocyclic Compounds, 4 or More Rings
-
Intercalating Agents
-
Naphthyridines
-
Thiophenes
-
Topoisomerase I Inhibitors
-
Tubulin Modulators
-
DNA
-
calf thymus DNA
-
DNA Topoisomerases, Type I