Interaction of dpyatriz and Cu/Zn-dpyatriz complexes with human telomere DNA: The role of G-quadruplex formation and its effect on antitumor and antitelomerase activity

Abstract

1,3,5-Triazine derivative of dipyridyl amine (dpyatriz) and the Cu(II), Zn(II) complexes have been prepared, characterized by CHN, IR, NMR and mass measurements and interacted with HTelo₈ and HTelo₂₀, the two types of human telomere repeat DNA (TTAGGG)n; n = 8, 20. The telomere DNAs have been treated with all three compounds (dpyatriz, Cu-dpyatriz and Zn-dpyatriz) under parallel/antiparallel and random coiled conditions. The interactions are followed by circular dichrosim measurements, fluorescent intercalator displacement (FID) assays and molecular docking studies through MOE program. The free ligand and its Cu(II) and Zn(II) complexes stabilize predominantly antiparallel G-quadruplex form under antiparallel and no salt conditions. The binding constant (K_b) values calculated for the ligand and complexes are in the range of 1.9 x 10⁵ M^-1 to 4.2 x 10⁷ M^-1 under various conditions show the higher affinity of G-quadruplex conformations. The FID assay using thiazole orange with HTelo₂₀ clearly depicts the G-quadruplex stabilization through strong binding mode. Also, all the three compounds dpyatriz, Cu-dpyatriz and Zn-dpyatriz show an intercalative mode of interaction with antiparallel G quadruplex DNA in molecular docking studies. The compounds show cytotoxicity with the IC₅₀ values in the range of 50 – 90 nM, and antitelomerase activity in the range of 5 to 10 μM.