Non-covalent complexes between bis-β-carbolines and double-stranded DNA: A study by electrospray ionization FT-ICR mass spectrometry (I) (original) (raw)
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Journal of the Brazilian Chemical Society, 2016
Quantitative interaction of twelve β-carboline derivatives with calf thymus deoxyribonucleic acid (ctDNA) using spectroscopic techniques was evaluated. The values of the binding constants (K b) obtained for the complexes formed with the ctDNA ranged from 3.30 × 10 2 to 1.82 × 10 6 mol L −1 , being the β-carbolines with the N,N-dimethylaminophenyl group at position 1 the ones which presented the highest K b values. The binding mode between the β-carbolines evaluated and ctDNA was proposed from the KI assay, competition with ethidium bromide, and DNA thermal denaturation profile (T m), where it was possible to infer that the evaluated alkaloids interact with ctDNA preferably via intercalation. Additionally, the correlation of K b values obtained with the IC 50 of seven human cancer cell lines was carried out. From this study, it was possible to observe a linear relation among most of the evaluated derivatives, obtaining r 2 values from 0.5360 to 0.9600. In addition, in silico molecular docking was performed to corroborate the experimental results.
Scientific Reports
Members of a novel class of anticancer compounds, exhibiting high antitumor activity, i.e. the unsymmetrical bisacridines (UAs), consist of two heteroaromatic ring systems. One of the ring systems is an imidazoacridinone moiety, with the skeleton identical to the structural base of Symadex. The second one is a 1-nitroacridine moiety, hence it may be regarded as Nitracrine’s structural basis. These monoacridine units are connected by an aminoalkyl linker, which vary in structure. In theory, these unsymmetrical dimers should act as double-stranded DNA (dsDNA) bis-intercalators, since the monomeric units constituting the UAs were previously reported to exhibit an intercalating mode of binding into dsDNA. On the contrary, our earlier, preliminary studies have suggested that specific and/or structurally well-defined binding of UAs into DNA duplexes might not be the case. In this contribution, we have revisited and carefully examined the dsDNA-binding properties of monoacridines C-1305, C...
Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA
Carcinogenesis, 1989
We present molecular mechanics simulation of the covalent interactions of the potent antitumor antibiotic belonging to the pyrrole[ 1,4]benzodiazepine class, anthramycin, with six deoxydecanucleotides, d(GCGCGCGCGC)*, d(Glo)d(C,,), (CCCCTCCCCC), and d(GGGGGTGGGG).d(CCCCACCCCC), in their minor grooves. The complexes are characterized by both a network of hydrogen bonds between the drug and the polynucleotide and good packing interactions. The DNA double helix in these complexes shows very minimal distortion, and interactions of the drug with the decanucleotides seem to be not very sensitive to the sequence variation around the site of complex formation. The conformational features in the complexes obtained are generally consistent with the experimentally derived conclusions by recent NMR and 2-D NOE studies. d(GCGCGTGCGC)*d(GCGCACGCGC), d(GCGCGAGCGC)*d(GCGCTCGCGC), d(GGGGGAGGGG).d-Anthramycin is a potent antitumor antibiotic and belongs to the pyrrolo[ 1,4] benzodiazepine class derived from Streptomyces refuineus.' The biological effectiveness of this drug has been proposed to result from its inhibition of nucleic acid synthesis through its covalent attachment to Several investigations have demonstrated the formation of a well-defined thermally labile covalent adduct with DNA.7-9 The drug is known to bind in the minor groove of the polynucleotides covering a 3-base-pair r e g i~n ,~~~J~J ' reacting specifically with DNA containing g~a n i n e .~-~ It does not react with mononucleotides, polynucleotides, and RNA not containing guanines. The complex has unusually high stability and survives conditions that disassociate the DNA complexes of most other antibiotics.l2 Anthramycin-modified DNA is inactivated as a template for RNA and DNA polymerase reactions and as a substrate for nuclease reactions.13J4 Earlier hydrolysis studies on the reaction of DNA with anthramycin had suggested C-11 on the drug to be a possible site of binding to DNA.12 Later studies by Ostrander et al.9 have confirmed the points of covalent attachment to be N2 of guanine and C-11 of anthramycin. On the basis of these observations, a CPK model of anthramycin-DNA adduct was proposed8 and in such a model the drug was shown to lie completely within the minor groove of the polynucleotide. Recently, several structural features of the adduct have been studied by 'H and 13C NMR spectros~opies.'~ The assignments of car
Molecular cancer therapeutics, 2005
The majority of DNA-binding small molecules known thus far stabilize duplex DNA against heat denaturation. A high, drug-induced increase in the melting temperature (Tm) of DNA is generally viewed as a good criterion to select DNA ligands and is a common feature of several anticancer drugs such as intercalators (e.g., anthracyclines) and alkylators (e.g., ecteinascidin 743). The reverse situation (destabilization of DNA to facilitate its denaturation) may be an attractive option for the identification of therapeutic agents acting on the DNA structure. We have identified the tumor-active benzoacronycine derivative S23906-1 [(+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2]acridin-7-one] as a potent DNA alkylating agent endowed with a helicase-like activity. Using complementary molecular approaches, we show that covalent binding to DNA of the diacetate compound S23906-1 and its monoacetate analogue S28687-1 induces a marked destabilization of...
Binding of Two Novel Bisdaunorubicins to DNA Studied by NMR Spectroscopy † , ‡
Biochemistry, 1997
In the search for new generations of anthracycline drugs, lower cytotoxic side effects and higher activity against resistant cancer cells are two major goals. A new class of bis-intercalating anthracycline drugs has been designed, synthesized, and shown to have promising activity against multidrug-resistant cells. Two daunorubicins symmetrically linked together via a p-xylenyl group, either at their N3′ (compound WP631) or N4′ sites (compound WP652), exhibit extraordinary DNA binding affinities. We have used high-resolution NMR studies to understand the DNA binding mode of these two new bis-daunorubicin anticancer compounds. The structures of the WP631-d(ACGTACGT) 2 and the WP652-d(TGTACA) 2 complexes have been determined by NOE-restrained refinement. WP631 binds strongly to the 5′-CG(A/T)(A/T)CG hexanucleotide sequence, with the aglycons intercalated between the two CpG sites at both ends of the hexanucleotide sequence. The overall conformation of the WP631-d(CGTACG) 2 part is remarkably similar to the crystal structure of the 2:1 complex of daunorubicin and d(CGTACG) 2 , as predicted previously [Gao, Y.-G., & Wang, A. H. J. (1996) J. Biomol. Struct. Dyn. 13, 103-117]. In contrast, the related bis-intercalator WP652 prefers the 5′-PyGTPu tetranucleotide sequence, with the aglycons intercalated between the PypG and TpPu sites. The binding of WP652 to DNA results in a severely distorted B-DNA duplex with the p-xylenyl tether moiety significantly protruded away from the bottom of the minor groove. While WP652 in some ways behaves similarly to other anticancer bis-intercalating antibiotics (e.g., triostine A and echinomycin), the detailed interactions between those two classes of bis-intercalators are quite different.
2016
In the present study the binding characteristics of Harmine with various DNA oligonuleotides have been studied by UV-Vis, fluorescence spectroscopy and molecular docking methods. UV absorption studies, Fluorescence quenching and Iodide quenching experiments confirmed intercalation type of binding of Harmine with short sequence specific DNA oligonucleotides. Binding constants of Harmine with sequence specific DNA oligomers were calculated by Fluorescence and absorption spectroscopic methods. For GC rich sequences binding constants were found in the order of 105 M-1 while for AT rich sequences it the values of binding constants were in the order of 103 M-1, which clearly indicated that Harmine showed greater interaction with GC rich sequences compared to AT rich sequences. The temperature effect studies and pH studies further supported the intercalative mode of binding. Molecular docking studies and the calculated thermodynamic parameters, Gibbs free energy (ΔG), Enthalpy change (ΔH) ...
Molecular BioSystems, 2013
Recently synthesis of programmable DNA ligands which can regulate transcription factors have increased the interest of researchers on the functional ability of DNA interacting compounds. A series of DNA interacting compounds are being designed which can differentiate between GC and AT rich DNA. In this study, we have studied the specificity of a few novel bisbenzimidazoles having different bi/tri-substituted phenyl rings, with DNA duplexes using spectroscopic methods. This study entails an integrative approach where we combine biophysical methods and molecular dynamics simulation studies to establish suitable scaffolds to target A/T DNA. We have designed a few analogues of Hoechst 33342 viz.; dimethoxy (DMA), trimethoxy (TMA), dichloro (DCA) and difluoro (DFA) functionalities and performed molecular docking of newly designed analogues with biologically relevant AT and GC rich DNA sequences. The docking studies, along with molecular dynamics (MD) simulations of d(ATATATATATATATAT) 2 , d(GA 4 T 4 C) 2 , d(GT 4 A 4 C) 2 and GC rich sequence: d(GCGCGCGCGCGCGCGC) 2 complexed with DMA, TMA and DFA, showed that these molecules have higher binding affinity towards AT rich DNA. None of these compounds exhibited an affinity to GC rich DNA rather we observed that these compounds destabilize GC rich DNA. The binding was characterized by strong stabilization of the polynucleotides against thermal strand separation in thermal melting experiments. New insights into the molecules binding to DNA have emerged from these studies. All the DNA binding ligands stabilized d(GA 4 T 4 C) 2 and d(GT 4 A 4 C) 2 more out of the five oligomers used for the study, suggesting that these ligands bind 'A 4 T 4 ' and 'T 4 A 4 ' strongly as compared to 'ATAT' base pairs.
DNA-Binding Properties of Bis-N-substituted Tetrandrine Derivatives
ACS Omega
A series of bis-N-substituted tetrandrine derivatives carrying different aromatic substituents attached to both nitrogen atoms of the natural alkaloid were studied with double-stranded model DNAs (dsDNAs) to examine the binding properties and mechanism. Variable-temperature molecular recognition studies using UV−vis and fluorescence techniques revealed the thermodynamic parameters, ΔH, ΔS, and ΔG, showing that the tetrandrine derivatives exhibit high affinity toward dsDNA (K ≈ 10 5 −10 7 M −1), particularly the bis(methyl)anthraquinone (BAqT) and bis(ethyl)indole compounds (BInT). Viscometry experiments, ethidium displacement assays, and molecular modeling studies enabled elucidation of the possible binding mode, indicating that the compounds exhibit a synergic interaction mode involving intercalation of one of the N-aryl substituents and interaction of the molecular skeleton in the major groove of the dsDNA. Cytotoxicity tests of the derivatives with tumor and nontumor cell lines demonstrated low cytotoxicity of these compounds, with the exception of the bis(methyl)pyrene (BPyrT) derivative, which is significantly more cytotoxic than the remaining derivatives, with IC 50 values against the LS-180, A-549, and ARPE-19 cell lines that are similar to natural tetrandrine. Finally, complementary electrochemical characterization studies unveiled good electrochemical stability of the compounds.
Alkaloid Escholidine and Its Interaction with DNA Structures
Biology
Berberine, the most known quaternary protoberberine alkaloid (QPA), has been reported to inhibit the SIK3 protein connected with breast cancer. Berberine also appears to reduce the bcl-2 and XIAP expression-proteins responsible for the inhibition of apoptosis. As some problems in the therapy with berberine arose, we studied the DNA binding properties of escholidine, another QPA alkaloid. CD, fluorescence, and NMR examined models of i-motif and G-quadruplex sequences present in the n-myc gene and the c-kit gene. We provide evidence that escholidine does not induce stabilization of the i-motif sequences, while the interaction with G-quadruplex structures appears to be more significant.