Structural and Thermodynamic Studies of the Interaction of Distamycin A with the Parallel Quadruplex Structure [d(TGGGGT)] 4 (original) (raw)
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Selective binding of distamycin a derivative to G-quadruplex structure [d(TGGGGT)]4
2010
Guanine-rich nucleic acid sequences can adopt G-quadruplex structures stabilized by layers of four Hoogsteen-paired guanine residues. Quadruplex-prone sequences are found in many regions of human genome and in the telomeres of all eukaryotic organisms. Since small molecules that target G-quadruplexes have been found to be effective telomerase inhibitors, the identification of new specific ligands for G-quadruplexes is emerging as a promising approach to develop new anticancer drugs. Distamycin A is known to bind to AT-rich sequences of duplex DNA, but it has recently been shown to interact also with G-quadruplexes. Here, isothermal titration calorimetry (ITC) and NMR techniques have been employed to characterize the interaction between a dicationic derivative of distamycin A (compound 1) and the [d(TGGGGT)] 4 quadruplex. Additionally, to compare the binding behaviour of netropsin and compound 1 to the same target, a calometric study of the interaction between netropsin and [d(TGGGGT)] 4 has been performed. Experiments show that netropsin and compound 1 are able to bind to [d(TGGGGT)] 4 with good affinity and comparable thermodynamic profiles. In both cases the interactions are entropically driven processes with a small favourable enthalpic contribution. Interestingly, the structural modifications of compound 1 decrease the affinity of the ligand toward the duplex, enhancing the selectivity.
Nucleosides, Nucleotides and Nucleic Acids, 2002
Homonuclear NMR techniques have been used to investigate the interactions of the minor groove binding agents distamycin A (Dist-A) and the related drug netropsin (Net) with three quadruplexes characterized by different groove widths: [d(TGGGGT)] 4 (Q1), [d(GGGGTTTTGGGG)] 2 (Q2), and d(GGGGTTGGGGTGTGGGGTTGGGG) (Q3). Netropsin has been found to be in a fast chemical exchange with all three kinds of quadruplexes, whereas Dist-A interacts tightly with Q1 and, at a less extent, with Q2. In order to determine the degree of selectivity of Dist-A for two-rather than four-stranded DNA, we titrated with Dist-A an equimolar solution of Q1 and the duplex d(CGCAAATTTGCG) 2 (D). This comparative 1 H-NMR study allowed us to conclude that Dist-A and, consequently, Net possess higher affinity for duplex DNA.
Nucleosides Nucleotides & Nucleic Acids, 2002
Homonuclear NMR techniques have been used to investigate the interactions of the minor groove binding agents distamycin A (Dist-A) and the related drug netropsin (Net) with three quadruplexes characterized by different groove widths: [d(TGGGGT)] 4 (Q1), [d(GGGGTTTTGGGG)] 2 (Q2), and d(GGGGTTGGGGTGTGGGGTTGGGG) (Q3). Netropsin has been found to be in a fast chemical exchange with all three kinds of quadruplexes, whereas Dist-A interacts tightly with Q1 and, at a less extent, with Q2. In order to determine the degree of selectivity of Dist-A for two-rather than four-stranded DNA, we titrated with Dist-A an equimolar solution of Q1 and the duplex d(CGCAAATTTGCG) 2 (D). This comparative 1 H-NMR study allowed us to conclude that Dist-A and, consequently, Net possess higher affinity for duplex DNA. *Corresponding
Targeting DNA quadruplexes with distamycin A and its derivatives: An ITC and NMR study
Biochimie, 2008
The use of small molecules that bind and stabilize G-quadruplex structures is emerging as a promising way to inhibit telomerase activity in tumor cells. In this paper, isothermal titration calorimetry (ITC) and 1 H NMR studies have been conducted to examine the binding of distamycin A and its two carbamoyl derivatives (compounds 1 and 2) to the target [d(TGGGGT)] 4 and d[AG 3 (T 2 AG 3 ) 3 ] quadruplexes from the Tetrahymena and human telomeres, respectively. The interactions were examined using two different buffered solutions containing either K þ or Na þ at a fixed ionic strength, to evaluate any influence of the ions present in solution on the binding behaviour. Experiments reveal that distamycin A and compound 1 bind the investigated quadruplexes in both solution conditions; conversely, compound 2 appears to have a poor affinity in any case. Moreover, these studies indicate that the presence of different cations in solution affects the stoichiometry and thermodynamics of the interactions.
Journal of the American Chemical Society, 2010
The study of DNA G-quadruplex stabilizers has enjoyed a great momentum in the late years due to their application as anticancer agents. The recognition of the grooves of these structural motifs is expected to result in a higher degree of selectivity over other DNA structures. Therefore, to achieve an enhanced knowledge on the structural and conformational requisites for quadruplex groove recognition, distamycin A, the only compound for which a pure groove binding has been proven, has been chemically modified. Surprisingly, structural and thermodynamic studies revealed that the absence of Coulombic interactions results in an unprecedented binding position in which both the groove and the 3′ end of the DNA are occupied. This further contribution adds another piece to the so far elusive puzzle of the recognition between ligands and DNA quadruplexes and will serve as a platform for a rational design of new groove binders.
Journal of Molecular Modeling, 2007
A 3D-QSAR analysis has been carried out by comparative molecular field analysis (CoMFA) on a series of distamycin analogs that bind to the DNA of drug-resistant bacterial strains MRSA, PRSP and VSEF. The structures of the molecules were derived from the X-ray structure of distamycin bound to DNA and were aligned using the Database alignment method in Sybyl. Statistically significant CoMFA models for each activity were generated. The CoMFA contours throw light on the structure activity relationship (SAR) and help to identify novel features that can be incorporated into the distamycin framework to improve the activity. Common contours have been gleaned from the three models to construct a unified model that explains the steric and electrostatic requirements for antimicrobial activity against the three resistant strains. Figure A unified CoMFA model for broad-spectrum DNA minor-groove binders
Synthesis of distamycin A polyamides targeting G-quadruplex DNA
Organic & Biomolecular Chemistry, 2006
A number of amide-linked oligopyrroles based on distamycin molecules have been synthesized by solid-state methods, and their interactions with a human intramolecular G-quadruplex have been measured by a melting procedure. Several of these molecules show an enhanced ratio of quadruplex vs. duplex DNA binding compared to distamycin itself, including one with a 2,5-disubstituted pyrrole group. Quadruplex affinity increases with the number of pyrrole groups, and it is suggested that this is consistent with a mixed groove/G-quartet stacking binding mode.
European Journal of Medicinal Chemistry, 2006
The anthracycline antibiotic daunomycin, having four fused rings and an amino sugar, is being used in the treatment of acute leukemia. Binding to DNA is generally believed to be essential for its activity. We have studied the interaction of daunomycin with DNA hexamer sequence d-(TGATCA) 2 by titrating up to two drug molecules per duplex using nuclear magnetic resonance spectroscopy. The solution structure of 2:1 drug to DNA complex based on two dimensional nuclear Overhauser enhancement (NOE) spectroscopy and molecular dynamics calculations has been studied. The change in conformation of drug molecule on binding to DNA, deoxyribose conformation and glycosidic bond rotation has been obtained. The absence of sequential NOE connectivities at d-T1pG2 and d-C5pA6 sites shows that the drug chromophore intercalates between these two base pairs. This is substantiated by intermolecular NOEs observed between nucleotide base protons and aromatic ring protons of drug molecule. A set of 17 intermolecular NOE interactions allowed the structure to be derived by restrained molecular dynamics simulations, which have been compared with that obtained by X-ray analysis. Several specific interactions between the drug and DNA protons are found to stabilize the formation of drug-DNA complex.
Journal of Medicinal Chemistry, 1995
I n the course of a study aimed a t the synthesis of pyrrole amidine carboxamide DNA-binding agents as novel pharmacological agents, a series of carbamoyl analogues of distamycin, containing a n increasing number of pyrrole units, have been obtained by total synthesis. The interaction of the tetrapyrrole carbamoyl 4 with the dodecamer d (C G C M W G C G) 2 in comparison with that of the corresponding formylamino analogue 3 has been examined by highresolution lH-NMR and molecular modeling. Either ligand binds to DNA in one-drug and symmetric two-drug modes a t low drug:DNA ratios, while at high ratios only the two-drug complex was observed. In this article, the structure of 2:l drugs DNA complexes has been studied by NMR and molecular modeling, which indicate that the two analogues bind the DNA in a similar fashion, in the minor groove of the B '-A A W region. In both complexes the two drugs are symmetrically placed along the complementary strands of DNA with the pyrrole ring of one molecule in close contact with those of the other one. Although another region of five consecutive AT base pairs is available, no evidence of sliding of drug molecules between different binding sites, as in the case of the 2:l complex of distamycin with the same dodecamer, is observed, thus indicating that increasing the number of N-methylpyrrolecarboxamide units from three to four cases a lengthening of the recognition sequence.
Biochemistry, 1990
It was demonstrated (previous paper) that replacement of methyl group by hydrogen (changing from T to U) in the major groove does not disrupt the array of bifurcated H bonds in the major groove. In this article, we summarize results of 2D N M R and molecular mechanic studies on the effect of a minor-groove-binding AOT-specific drug on the structure d(GA4T4C)2. A distamycin analogue (Dstf) was used for this study. It is shown that Dst2 binds to the minor groove of d(GA4T4C)2 mainly driven by van der Waals interaction between AT pairs and the drug; as a consequence, an array of bifurcated H bonds can be formed in the minor groove between amide/amino protons of Dst2 and AT pairs of DNA. NOESY data suggest that Dst2 predominantly binds at the central 5 AT pairs. NOESY data also reveal that, upon drug binding, d(GA4T4C)2 does not undergo any significant change in conformation from the free state; i.e., propeller-twisted AT pairs are still present in D N A and hence the array of bifurcated H bonds must be preserved in the major groove. NOESY data for the A5-T6 sequence also indicate that there is little change in junction stereochemistry upon drug binding. I t is well-known that the presence of A/T tracts at regular intervals of 10 base pairs in a DNA polymer can cause macroscopic DNA bending (Hagerman, 1985; Koo et al., 1986; Marini et al., 1982). It is also known that the dimer sequence connecting two neighboring A/T tracts is extremely important; the cases in point are two Hagerman polymers, Le., poly[d-(GA4T4C),] is bent while poly[d(GT,A,C),] is straight (Hagerman, 1986). These studies suggested that two factors primarily contribute to the observed bending in DNA polymers with A/T tracts: (i) the structural pecularity of the A/T tract and (ii) the stereochemistry of the dimer sequence that connects two neighboring A/T tracts. However, details about these two structural aspects could not be obtained from the experimental studies on macroscopic DNA bending because the techniques used in these studies (gel electrophoresis, electron microscopy, etc.) could only provide information at the macroscopic level. In an attempt to visualize the structural roles of the A/T tracts and the junction sequence on DNA bending, we initiated two-dimensional nuclear magnetic resonance (2D NMR) studies on two decamers, d(GA4T4C), and d(GT4A,C),. The results of these studies were previously reported (