engleski

Mechanism of action of three novel dicationic bis(phenylamidine) derivatives

Three novel DNA minor groove binders: 2, 5-bis(4-amidinophenyl)-3, 4-ethylenedioxy-thiophene dihydrochloride (1), 2, 5-bis[4-(N-isopropylamidino)phenyl)]-3, 4-ethylene-dioxythiophene dihydrochloride (2) and 2, 5-bis[4-(2-imidazolino)phenyl]-3, 4-ethylene-dioxythiophene dihydrochloride (3) have been synthesized and evaluated for antiproliferative activity.According to the UV/vis titrations compounds 1-3 show high affinity (Ks > 105 M– 1) toward ds-DNA, and accordingly cause strong thermal stabilisation of DNA ( Tm > 12 °C). For all studied compounds circular dichroism (CD) titrations strongly support DNA minor groove binding as a dominant interaction. Furthermore, compounds 1-3 and DNA- minor groove binder Hoechst 33258, at concentration of 10-4 to 10-7 M, were tested against panel of 7 solid tumour cell lines (MCF-7, NCI-H358, CaCo-2, HEp-2, HeLa, AGS, and MiaPaCa). Compound 3 exhibits the best antiproliferative efficiency at all tested doses compared to control. By monitoring internalization dynamics we notice that compound 3 penetrates in to the live HeLa cell and localises in to the nucleus after 90 minutes of incubation. Cell cycle analysis showed that compound 3 at equitoxic concentration (5*10– 5 M) arrested HeLa cells in G1 and G2/M phases at all 3 tested times (24, 48, 72 h) at statistically significant level (p < 0.05), at variance to the effect observed for Hoechst 33258, which stopped cell cycle in S phase under the same conditions.

DNA- minor groove binder; Hoechst 33258; bis(phenylamidine) derivatives; antiproliferative effects; cell cycle; HeLa cells

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