Binding of Two Novel Bisdaunorubicins to DNA Studied by NMR Spectroscopy † , ‡ (original) (raw)
Related papers
Chemico-Biological Interactions, 2003
DNA is a target molecule for anthracycline anticancer drugs. We have used new anthracycline derivatives, bisdaunorubicin (WP631) and its monomeric analogues (WP700 serie), and look if there was a relation between the drug binding affinity to naked DNA and to cell nucleus in the cell with its cytotoxicity. Circular dichroism (CD) and fluorescence were used to follow the interaction of anthracycline derivatives with naked DNA and cell nuclei. WP631 interacts with DNA at two distinct stoichiometries, 6:1 and 3:1 base pair (bp)/WP631 molecule (3:1 and 1.5:1 per anthracycline rings). Monomeric daunorubicin (DNR) with its amino sugar N-bound to amino-and nitro-substituted benzyl moiety, representing p -xylenyl linker present in WP631 bisintercalator, is much more binding to DNA than DNR or WP631. These findings are supported by the study of drug binding by nuclei of K562 cells. Around 70% of WP700 intercalate to nucleus DNA in the steady-state, while only 45% of DNR intercalate DNA in the cell. The binding of WP631 by K562 cells is even less effective (Â/20%). WP 700 compounds, which are very similar to each other in their binding to DNA, self-association and cell accumulation, differ very distinctly in their cytotoxicity power. The most effective compounds are amino-benzyl derivatives of WP 700 series. The nitro-benzyl compounds have very low toxicity, even if they bind to DNA with similar power with that of the amino derivatives. The comparison of the all data clearly indicates no relation between cytotoxicity of the drug and its ability to intercalate DNA. #
A New Bisintercalating Anthracycline with Picomolar DNA Binding Affinity
Journal of Medicinal Chemistry, 2005
A new bisintercalating anthracycline (WP762) has been designed, in which monomeric units of daunorubicin have been linked through their amino groups on the daunosamine moieties using an m-xylenyl linker. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP762 to DNA. The binding constant for the interaction of WP762 with herring sperm DNA was determined to be 7.3 (±0.2) × 10 12 M −1 at 20°C. The large favorable binding free energy of −17.3 kcal mol −1 was found to result from a large negative enthalpic contribution of −33.8 kcal mol −1 and an opposing entropic term (−TΔS = +16.5 kcal mol −1). A comparative molecular modeling study rationalized the increased binding by the m-xylenyl linker of WP762 positioning in the DNA minor groove compared to the p-xylenyl linker found in WP631, the first bis-anthracycline of this type. The cytotoxicity of WP762 was compared to that of other anthracyclines in Jurkat T lymphocytes. These studies, together with an analysis of the cell-cycle traverse in the presence of WP762, suggest that in these cells the new drug is more cytotoxic than the structurally related WP631.
Anthracycline binding to DNA. High-resolution structure of d(TGTACA) complexed with 4'-epiadriamycin
European Journal of Biochemistry, 1992
Crystallographic methods have been applied to determine the high-resolution structure of the complex formed between the self-complementary oligonucleotide d(TGTACA) and the anthracycline antibiotic 4-epiadriamycin. The complex crystallises in the tetragonal system, space group P4,212 with c1 = 2.802 nm and c = 5.293 nm, and an asymmetric unit consisting of a single D N A strand, one drug molecule and 34 solvent molecules. The refinement converged with an R factor of 0.17 for the 2381 reflections with F a 3oF in the resolution range 0.70-0.14 nm. Two asymmetric units associate such that a distorted B-DNA-type hexanucleotide duplex is formed incorporating two drug molecules that are intercalated at the TpG steps. The amino sugar of 4'-epiadriamycin binds in the minor groove of the duplex and displays different interactions from those observed in previously determined structures. Interactions between the hydrophilic groups of the amino sugar and the oligonucleotidc are all mediated by solvent molecules. Ultraviolet melting measurements and comparison with other anthracycline-DNA complexes suggest that these indirect interactions have a powerful stabilising effect on the complex.
Nucleic Acids Research, 1979
Interaction of DNA with the analogs of the antibiotic distazycin A having different numbers of pyrrolcarboxamide groups and labeled with dansyl was studied. The bindin isoterms of the analogs to synthetic polydeoxyribonucleotides were obtained. Analysis of the experimental data leads to the following conclusions: (1) the free energy of binding of the analogs to po1y(dA)-poly(dT) depends linearly on the number of amide groups in the molecule of the analog whereas attachment of each pyrrolcarboxamide group produces changes of 2 kcal/mole in the free energy; (2) attachment of a pyrrolcarboxamide unit to the GO pair results in the free energy change of 0.95 kcal/mole; (3) the binding of analogs to poly(dA).poly(dT) is a cooperative process, presumbly, dependent on conformational changes induced by the binding of analogs to DNA.
Journal of Molecular Biology, 1997
The three-dimensional solution structure of duocarmycin SA in complex with d-(G 1 ACTAATTGAC 11 )Á d-(G 12 TCATTAGTC 22 ) has been determined by restrained molecular dynamics and relaxation matrix calculations using experimental NOE distance and torsion angle constraints derived from 1 H NMR spectroscopy. The ®nal input data consisted of a total of 858 distance and 189 dihedral angle constraints, an average of 46 constraints per residue. In the ensemble of 20 ®nal structures, there were no distance constraint violations >0.06 A Ê or torsion angle violations >0.8 . The average pairwise root mean square deviation (RMSD) over all 20 structures for the binding site region is 0.57 A Ê (average RMSD from the mean: 0.39 A Ê ). Although the DNA is very B-like, the sugar-phosphate backbone torsion angles b, e, and z are distorted from standard values in the binding site region. The structure reveals site-speci®c bonding of duocarmycin SA at the N3 position of adenine 19 in the AT-rich minor groove of the duplex and binding stabilization via hydrophobic interactions. Comparisons have been made to the structure of a closely related complex of duocarmycin A bound to an AT-rich DNA duplex. These results provide insights into critical aspects of the alkylation site selectivity and source of catalysis of the DNA alkylating agents, and the unusual stability of the resulting adducts.
Journal of Pharmaceutical Sciences, 1989
A group of pseudopeptides, molecular combination of the natural antitumor agents distamycin or netropsin and the anilinoacridine chromophore (which is related to the synthetic antileukemic drug amsacrine) has been synthesized. Their DNA binding properties were determined and discussed in terms of their structural differences and in relation to their observed base-dependent binding. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the netropsin or distamycin residue resides in the DNA minor groove. Cytostatic and cytotoxic activities against a murine cell line are reported, as well as significant differences in the inhibition of DNA synthesis. Nt D5t.A ship of sequence-directed DNA effectors. Results and Discussion Chemistry-N-Methyl-2-pyrrole carboxylic acid was esterified with methyl iodide, and then nitrated with nitric acid in acetic anhydride (see Scheme I). Separation by column chromatography gave the methyl N-methy 1-4-nitro-2-pyrrole carboxylate (Z), the 5-nitro isomer, and the dinitro derivative. The nitro ester 2 was reduced to the amine 3, which was condensed with ditertbutyldicarbonate [(BOC),O] to give the BOC-protected ester 4. However, it should be pointed out here that the unstable air-sensitive amino acid 3 could be easily
Designing DNA Binding Antitumor Antibiotics With Structure Determination: A Systems Approach
2008
Hoechst-33258 was designed in order to furnish GC-sequence binding drugs. By closely analyzing the DNA binding structural parameters needed in the structure of a drug, it was effectively concluded that by replacing C-atoms with a more electronegative atoms like N atoms would afford the change in DNA sequence specificity of the DNA minor groove binding antitumor compounds. The structural analysis of modified drug: DNA complexes has revealed the change of DNA sequence specificity from AT to GC. In another case, the derivatives of Hoechst-33258 with N or O-atom at selected positions resulted in the GCsequence selective DNA binding. With systems approach, a few selectively chosen C-atoms in a pyrrole or benzimidazole rings were replaced with H-bond donor atoms like O or N atoms. This DNA sequence specificity has also resulted in the enhanced DNA topoisomerase inhibiting profile, needed for antitumor activity.
European Journal of Medicinal Chemistry, 2014
The interaction of small molecules with DNA plays an essential role in many biological processes. As DNA is often the target for majority of anticancer and antibiotic drugs, study about the interaction of drug and DNA has a key role in pharmacology. Moreover, understanding the interactions of small molecules with DNA is of prime significance in the rational design of more powerful and selective anticancer agents. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. For these last the DNA recognition is a critical step in their anti-tumor action and the intercalation is not only one kind of the interactions in DNA recognition but also a pivotal step of several clinically used anti-tumor drugs such as anthracyclines, acridines and anthraquinones. To push clinical cancer therapy, the discovery of new DNA intercalators has been considered a practical approach and a number of intercalators have been recently reported. The intercalative binding properties of such molecules can also be harnessed as diagnostic probes for DNA structure in addition to DNA-directed therapeutics.
High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA
Journal of Molecular Biology, 1997
The three-dimensional solution structure of duocarmycin SA in complex with d-(G 1 ACTAATTGAC 11)Á d-(G 12 TCATTAGTC 22) has been determined by restrained molecular dynamics and relaxation matrix calculations using experimental NOE distance and torsion angle constraints derived from 1 H NMR spectroscopy. The ®nal input data consisted of a total of 858 distance and 189 dihedral angle constraints, an average of 46 constraints per residue. In the ensemble of 20 ®nal structures, there were no distance constraint violations >0.06 A Ê or torsion angle violations >0.8. The average pairwise root mean square deviation (RMSD) over all 20 structures for the binding site region is 0.57 A Ê (average RMSD from the mean: 0.39 A Ê). Although the DNA is very B-like, the sugar-phosphate backbone torsion angles b, e, and z are distorted from standard values in the binding site region. The structure reveals site-speci®c bonding of duocarmycin SA at the N3 position of adenine 19 in the AT-rich minor groove of the duplex and binding stabilization via hydrophobic interactions. Comparisons have been made to the structure of a closely related complex of duocarmycin A bound to an AT-rich DNA duplex. These results provide insights into critical aspects of the alkylation site selectivity and source of catalysis of the DNA alkylating agents, and the unusual stability of the resulting adducts.
Scientific Reports
Triazoloacridinone C-1305, a potent antitumor agent recommended for Phase I clinical trials, exhibits high activity towards a wide range of experimental colon carcinomas, in many cases associated with complete tumor regression. C-1305 is a well-established dsDNA intercalator, yet no information on its mode of binding into DNA is available to date. Herein, we present the NMR-driven and MD-refined reconstruction of the 3D structures of the d(CGATATCG)2:C-1305 and d(CCCTAGGG)2:C-1305 non-covalent adducts. In both cases, the ligand intercalates at the TA/TA site, forming well-defined dsDNA:drug 1:1 mol/mol complexes. Orientation of the ligand within the binding site was unambiguously established by the DNA/ligand proton-proton NOE contacts. A subsequent, NMR-driven study of the sequence-specificity of C-1305 using a series of DNA duplexes, allowed us to confirm a strong preference towards TA/TA dinucleotide steps, followed by the TG/CA steps. Interestingly, no interaction at all was obs...