Cytotoxicities, telomerase and topoisomerases I inhibitory activities and interactions of terpyridine derivatives with DNAs

Abstract

A novel compound 4-methyl-7-{[4-(2,2′:6′,2″-terpyridin-4′-yl)benzyl]amino}-2H-chromen-2-one(1) was synthesized, and its DNA-binding properties, cytotoxicity, and telomerase and Topo I inhibitory activities were evaluated. For comparison, the anti-proliferative and Topo I inhibitory activities of another two analogues 2 and 3 were also investigated. Compound 1 is able to stabilize the structures of human telomere(h-tert) and promoter(c-myc and c-kit2) G-quadruplexes and h-tert i-motif. The association constants(K _b) are about 10⁶ L/mol for h-tert G-quadruplex and i-motif, while the values are about 10⁵ L/mol for both promoter G-qaudruplexes and calf thymus DNA(ct-DNA). The binding of compound 1 induces the change of h-tert G-quadruplex from hybrid to antiparallel structure and exhibits 88.7% inhibition of telomerase activity at 8 μmol/L. Both compounds 1 and 3 inhibit significantly Topo I-mediated relaxation of pBR322 DNA. Compounds 1 and 2 show a high inhibitory efficacy on HepG2 and MCF-7 cancer cell lines with IC₅₀ values of about 10^–6 mol/L. The three compounds also induce a delay of cell cycle progression. The coumarin group is vital for improving the biological activity of terpyridine derivatives.

Keywords

Terpyridine / Coumarin / Quadruplex / Telomerase / Topoisomerase I

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