Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Structural Transition in the Human Telomeric DNA Sequence d[(TTAGGG)4] upon interaction With Putative Anticancer Agents, Sanguinarine And Ellipticine
Even though there have been several studies of interaction between DNA and antcancer agents (1-4), not very much is known about their interactions with the telomeric regions of chromosomes. Guanine rich sequences fold into a non-canonical structure known as G-quartet in the presence of appropriate salt concentration. G-quartets stack on one another to form G-quadruplex. G-rich sequences are found in the telomeric regions of chromosomes and play an important role in chromosome duplication. They are potential targets for anticancer drugs (5). Here we have reported the structural transition of G-quadruplex induced by two putative anticancer agents, Sanguinarine (SGR) and Ellipticine (ELP), from plant sources.
SGR binds with the human telomeric DNA sequence d[(TTAGGG)4] (H24) in the presence of K+ with a 2:1 binding stoichiometry possibly via the end stacking mechanism. Studies based on CD spectroscopy have indicated that at higher concentration (above 20 μM) SGR induces a structural alteration in H24. The structure of H24 changes from the mixed Type-I conformation to the Na+ -conformation (6). ELP also binds with H24. At lower concentrations (100 nM) it binds with 3:2 stoichiometry (ELP : H24) as suggested from Jobs’ Plot based on fluorescence measurements. But at higher ellipticine concentration (8 μM), it binds with a stoichiometry of 2:1 (ELP : H24) and a relatively lower affinity. CD spectroscopic studies suggest that at higher concentrations of drug, H24 undergoes a structural change from the mixed Type-I conformation to the Na+ -conformation. Similar studies from other group (7) along with our results suggest that G-quadruplex interacting drugs probably induce a structural change at higher drug concentration. It could be a plausible molecular mechanism of the action of G-quadruplex binding drugs that interferes with normal biological activities.
Saptaparni Ghosh1, *