Abstract
A cyclic naphthalene diimide (cyclic NDI, 1), carrying a benzene moiety as linker chain, was synthesized and its interaction with G-quadruplex DNAs of a-core and a-coreTT as a human telomeric DNA, c-kit and c-myc as DNA sequence at promoter region, or thrombin-binding aptamer (TBA) studied based on UV-VIS and circular dichroism (CD) spectroscopic techniques, thermal melting temperature measurement, and FRET-melting assay. The circular dichroism spectra showed that 1 induced the formation of different types of G-quadruplex DNA structure. Compound 1 bound to these G-quadruplexes with affinities in the range of 106–107 M−1 order and a 2:1 stoichiometry. Compound 1 showed 270-fold higher selectivity for a-core than dsDNA with a preferable a-core binding than a-coreTT, c-kit, c-myc and TBA in the presence of K+, which is supported by thermal melting studies. The FRET-melting assay also showed that 1 bound preferentially to human telomeric DNA. Compound 1 showed potent inhibition against telomerase activity with an IC50 value of 0.9 μM and preferable binding to G-quadruplexes DNA than our previously published cyclic NDI derivative 3 carrying a benzene moiety as longer linker chain.
Highlights
Guanine-rich DNA sequences which mainly originate in important regions of the oncogene promoters, telomere, mRNA, ribosomal DNA, and thrombin-binding aptamer (TBA) can form
G-quadruplex DNAs is known to be formed at promoter regions of the human oncogene that can regulate gene expression at the transcriptional level [3]
It has been reported that guanine-rich oligonucleotides could form G-quadruplexes via Hoogsteen hydrogen bonding among four guanine bases arranged in a square planar configuration [4]
Summary
Guanine-rich DNA sequences which mainly originate in important regions of the oncogene promoters, telomere, mRNA, ribosomal DNA (rDNA), and thrombin-binding aptamer (TBA) can form. DNA shows diverse structural polymorphism; G-quadruplex DNA can be either parallel or antiparallel, even both conformations (termed hybrid) in some cases [5,6] This G-quadruplex DNA can fold as a mixture of several different quadruplex forms depending on DNA sequence and extrinsic cation which offers a platform to induce and stabilize the quadruplexes by using small organic molecules [5,6]. G-quadruplex-binders include porphyrin derivatives, oxazoles, perylene derivatives and similar systems [10] that have fused π-ring systems within the molecule and showed various binding selectivity with the G-quadruplexes’ DNA structure. G-quadruplex DNA structure-specific and selective binding ligands [6,9] which are important for drug development, cancer research and therapeutic application studies. We have characterized the binding selectivity and stability of 1 to G-quadruplexes’ DNA present in the promoter region (c-myc and c-kit), thrombin binding aptamer (TBA) and human telomeric region (a-core and a-coreTT) by UV-Vis spectroscopy, circular dichroism (CD) spectroscopy, thermal melting studies, TRAP assay and FRET-melting assay [23] experiments
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