Synthesis, DNA/RNA affinity and antitumour activity of new aromatic diamidines linked by 3,4-ethylenedioxythiophene

A series of novel 2,5-bis(amidinophenyl)-3,4-ethylenedioxythiophenes (5–10 and 15) has been synthesized. Compounds 5–10 bind to the DNA minor groove as the dominant binding site and strongly stabilize the double helix of ct-DNA. Surprisingly, the same compounds also thermally stabilize ds-RNA, whereby most of them form stacked dimers along the RNA double helix. The only exception is compound 15 which, due to its structural features, showed no interaction with DNA or RNA. Compounds 5–10 have shown a moderate to strong cytotoxic effect (GI50 = 1.5–9.0 μM) on a panel of seven tumour cell lines. The diimidazoline derivative 9, due to its highest inhibitory potential on the growth of all tested tumour cell lines, was investigated in more detail by testing its ability to enter into cells and influence the cell cycle. Compound 9 (5 μM) was internalized successfully in cell cytoplasm during a 30-min incubation period, followed by nuclear localization upon 90-min incubation. Significant arrest in HeLa cells in the G2/M phase, shown by cell cycle analysis at an equitoxic (50 μM) concentration, suggests interaction of a studied compound with cellular DNA as the main mode of biological action.

Figure optionsDownload as PowerPoint slideResearch highlights
► A series of novel 2,5-bis(amidinophenyl)-3,4-ethylenedioxythiophenes has been synthesized.
► The new synthesized compounds strongly stabilize the double helix of ct-DNA and surprisingly ds-RNA.
► A tested compounds have shown a moderate to strong cytotoxic effect (GI50 = 1.5–9.0 μM) on a panel of seven tumour cell lines.