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The binding interactions of (-)-daunorubicin (WP900), a newly synthesized enantiomer of the anticancer drug (+)-daunorubicin, with right- and left-handed DNA, have been studied quantitatively by equilibrium dialysis, fluorescence spectroscopy, and circular dichroism. (+)-Daunorubicin binds selectively to right-handed DNA, whereas the enantiomeric W...
Citations
... The anticancer drug daunorubicin, implicated in the destruction of multidrug-resistant cancer cells, is also a curious case regarding the BZ equilibrium. WP900 is (-)-daunorubicin that favors the conversion of B-DNA into Z-DNA (Qu et al. 2000), while (+)-daunorubicin destabilizes Z-DNA by selective binding to B-DNA, which shifts the equilibrium from Z-DNA to B-DNA. (+)daunorubicin is known to intercalate into DNA, used in cancer therapy (Fuertes et al. 2006). ...
... In contrast to simple planar aromatic molecules, there is only limited knowledge about the interaction of helically chiral aromatic ligands with DNA at the molecular or cellular level [11][12][13]. ...
In this contribution, we focused on a fundamental study targeting the interaction of water-soluble [6] helicene derivative 1 (1-butyl-3-(2-methyl [6] helicenyl)-imidazolium bromide) with double-stranded (ds) DNA. A synthetic 30-base pair duplex, plasmid, chromosomal calf thymus and salmon DNA were investigated using electrochemistry, electrophoresis and spectroscopic tools supported by molecular dynamics (MD) and quantum mechanical approaches. Both experimental and theoretical work revealed the minor groove binding of 1 to the dsDNA. Both the positively charged imidazole ring and hydrophobic part of the side chain contributed to the accommodation of 1 into the dsDNA structure. Neither intercalation into the duplex DNA nor the stable binding of 1 to single-stranded DNA were found in topoisomerase relaxation experiments with structural components of 1, i.e. [6] helicene (2) and 1-butyl-3-methylimidazolium bromide (3), nor by theoretical calculations. Finally, the binding of optically pure enantiomers (P)-1 and (M)-1 was studied using circular dichroism spectroscopy, isothermal titration calorimetry and UV Resonance Raman (UVRR) methods. Using MD and quantum mechanical methods, minor groove and semi-intercalation were proposed for compound 1 as the predominant binding modes. From the UVRR findings, we also can conclude that 1 tends to preferentially interact with adenine and guanine residues in the structure of dsDNA.
... Since DNA has a chiral double-helical structure, enantiomers can have different binding abilities and a high level of discrimination between left-handed and right-handed DNA, which makes them perfect for selective targeting of cells (refer to Figure 10 below). There is evidence that certain chiral metal complexes have the ability to not only distinguish between the handedness of DNA before intercalating into the DNA, but also change the shape of the DNA to the chiral form preferred by each ligand (20). ...
This study considered the preparation of a new DNA binding Ruthenium polypyridyl complex possessing an infrared active nitrile group. The binding abilities of a novel Ruthenium complex, [Ru(TMP)2DPPZ-10-CN], to various forms of DNA—both canonical and non-canonical—were examined by performing multiple DNA titrations. DNA is of great interest as it is the carrier of genetic information for all living things. Damage to DNA can have drastically detrimental effects, so the study of its structure and replication is of great importance. Two non-canonical structures that are important are the G-quadruplex and i-motif which form at the telomeric and regulatory regions of genes, respectively, and have the ability to block telomerase activity and influence transcription. The complex was synthesized by microwave irradiation and purified using a silica column and an ion exchange with Amberlite 402. Six titrations were, then, performed with salmon sperm dsDNA, guanine monophosphate (GMP), G4T4G4, human telomere G-quadruplex, i-motif C5T3, and i-motif C30. The complex was found to favor non-canonical structures, particularly the G-quadruplex structure, because of its high [bp]/[Ru] concentrations. The higher concentration of base pairs or structures per Ruthenium molecule indicated that the complex had a high binding affinity for that particular DNA structure. These results support the notion that Ruthenium metal complexes can be used for theragnostic purposes and can be used to target the telomeric region of genes where G-quadruplex structures can be found and influence transcription initiation and inhibit telomerase activity.
... Since DNA has a chiral double-helical structure, enantiomers can have different binding abilities and a high level of discrimination between left-handed and right-handed DNA, which makes them perfect for selective targeting of cells (refer to Figure 10 below). There is evidence that certain chiral metal complexes have the ability to not only distinguish between the handedness of DNA before intercalating into the DNA, but also change the shape of the DNA to the chiral form preferred by each ligand (20). ...
This study considered the preparation of a new DNA binding Ruthenium polypyridyl complex possessing an infrared active nitrile group. The binding abilities of a novel Ruthenium complex, [Ru(TMP)2DPPZ-10-CN], to various forms of DNA—both canonical and non-canonical—were examined by performing multiple DNA titrations. DNA is of great interest as it is the carrier of genetic information for all living things. Damage to DNA can have drastically detrimental effects, so the study of its structure and replication is of great importance. Two non-canonical structures that are important are the G-quadruplex and i-motif which form at the telomeric and regulatory regions of genes, respectively, and have the ability to block telomerase activity and influence transcription. The complex was synthesized by microwave irradiation and purified using a silica column and an ion exchange with Amberlite 402. Six titrations were, then, performed with salmon sperm dsDNA, guanine monophosphate (GMP), G4T4G4, human telomere G-quadruplex, i-motif C5T3, and i-motif C30. The complex was found to favor non-canonical structures, particularly the G-quadruplex structure, because of its high [bp]/[Ru] concentrations. The higher concentration of base pairs or structures per Ruthenium molecule indicated that the complex had a high binding affinity for that particular DNA structure. These results support the notion that Ruthenium metal complexes can be used for theragnostic purposes and can be used to target the telomeric region of genes where G-quadruplex structures can be found and influence transcription initiation and inhibit telomerase activity.
... One such example includes the use of an annulation reaction that improves the stability of phenanthridine derivatives [38]. Parenty and coworkers carried out annulation of the heteroaromatic middle ring and reported dihydroimidazophenanthridinium (DIP) derivatives (55)(56)(57)(58). The derivatives showed improved metabolic stability while retaining cytotoxicity. ...
... The computational analysis suggests that the synthesized compounds bind preferentially in the minor groove of DNA for AT and GC rich nucleotide sequence, and in the major groove of DNA for mixed nucleotide sequence [55]. Naphthalimides are well-known DNA photocleavers and cytotoxic agents [56][57][58][59][60][61][62][63][64][65][66]. The study performed by Yang et al. [67] investigates the DNA binding potential of a series of bioactive chiral heterocyclic naphthalimide derivatives (122)(123)(124). ...
Abstract:
Since the discovery of DNA intercalating agents (by Lerman, 1961), a growing number of organic, inorganic, and metallic compounds have been developed to treat life-threatening microbial infections and cancers. Fused heterocycles are amongst the most important group of compounds that have the ability to interact with DNA. DNA intercalators possess a planar aromatic ring structure that inserts itself between the base pairs of nucleic acids. Once inserted the aromatic structure make van der Waals interactions and hydrogen-bonding interactions with the base pairs. The DNA intercalator may also contain an ionizable group that can form ionic interactions with the negatively charged phosphate backbone. After the intercalation, other cellular processes could take place, leading ultimately to cell death. The heterocyclic nucleus present in the DNA intercalators can be considered as a pharmacophore that plays an instrumental role in dictating the affinity and selectivity exhibited of these compounds. In this work, we have carried out a revision of small organic molecules that bind to the DNA molecule via intercalation and cleaving and exert their antitumor activity. A general overview of the most recent results in this area, paying particular attention to compounds that are currently under clinical trials is provided. Advancement in spectroscopic techniques studying DNA interaction can be examined in depth, yielding important information on structure-activity relationships. In this comprehensive review, we have focused on the introduction to fused heterocyclic agents with DNA interacting features, from medicinal point of view. The structure activity relationships points, cytotoxicity data, and binding data and future perspectives of medicinal compounds have been discussed in detail.
Keywords: Fused heterocyclic, Anticancer, Intercalation, Ellipticine, Planar molecule, DNA, Structure activity relationships (SAR)
... In order to perform a quantitative comparison of the binding strength of A 3 with CT-DNA, the binding constant (K) was calculated according to the Langmuir formula in Equation (A.1). 29 Based on the procedure of Qu et al 30 it is considered that DNA and DRUG only create a single complex DNA.DRUGm. ...
Aim
A new Ag(I) complex (A3) was synthesized and evaluated for its anticancer activity against human cancer cell lines.
Materials and Methods
The complex A3 was characterized by ¹H, ¹³C, and ³¹P nuclear magnetic resonance (NMR), infrared (IR) spectra, elemental analysis, and X-ray crystallography. The interaction of the complex with CT-DNA was studied by electronic absorption spectra, fluorescence spectroscopy, and cyclic voltammetry; cell viability (%) was assessed by absorbance measurement of the samples.
Results
The interaction mode of the complex A3 with DNA is electrostatic, and this complex shows good potential in anticancer properties against HCT 116 (human colorectal cancer cells) and MDA-MB-231 (MD Anderson-metastatic breast) cell lines with 0.5 micromolar concentrations.
Conclusion
The Ag(I) complex could interact with DNA noncovalently and has anticancer properties.
... At a high-order level, the common helix structure of doublestranded DNA (see Fig. 1 for the schematic representation) leads to supramolecular chiral properties, as exemplified by the righthanded (for the common B-DNA form) or the left-handed (for the uncommon Z-DNA form) helical arrangements depending on the ribose conformation [11]. Chaires and co-workers reported the most representative example of the helix handedness impact on the enantioselective binding of chiral DNA ligands: one enantiomer of daunorubicin binds selectively to B-DNA conformation, whereas the other enantiomer prefers the Z-DNA helix [20]. Other nucleic acid motifs such as hairpins, G-quadruplex or three-way junctions ( Fig. 1) also display stereoselective capabilities depending on their three-dimensional architectures. ...
Naturally occurring polymers (and their derivatives) such as polysaccharides and proteins are very popular chiral selectors in analytical sciences. In contrast, nucleic acids have received much less attention in the enantiomeric analysis field. However, some significant advances have been accomplished during the last thirty years. The present review covers these different contributions in the development of both chiral sensor and separation systems. They rely on the use of either nonspecific nucleic acid molecules or target-specific oligonucleotides. The main practical factors as well as the applicability features of the reported nucleic acid-based enantioselective tools are summarized. Some possible routes for improvement are also suggested.
... The anticancer drug (+)daunorubicin, binds selectively to B-DNA and was found to be an allosteric effector. It converted a [poly(dGdC)] 2 in the Z-DNA conformation to its intercalated B-DNA form [119,120]. More recently, quinacrine and 9amino-acridine were observed to bind strongly to B-DNA and decrease the rate of transition from B-DNA to Z-DNA, in addition to converting the left handed poly(dGm 5 -dC) back to the right-handed B-DNA form [121]. The tetrapeptide, lysyl tryptophenyl glycyl lysine O-tert butyl ester (KWGK) was also shown to convert poly(dG-m 5 dC) Z-DNA to its B-DNA form under low salt conditions as determined by CD spectroscopy. ...
Genome integrity is essential for proper cell function such that genetic instability can result in cellular dysfunction and disease. Mutations in the human genome are not random, and occur more frequently at "hotspot" regions that often co-localize with sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures. Non-B DNA-forming sequences are mutagenic, can stimulate the formation of DNA double-strand breaks, and are highly enriched at mutation hotspots in human cancer genomes. Thus, small molecules that can modulate the conformations of these structure-forming sequences may prove beneficial in the prevention and/or treatment of genetic diseases. Further, the development of molecular probes to interrogate the roles of non-B DNA structures in modulating DNA function, such as genetic instability in cancer etiology are warranted. Here, we discuss reported non-B DNA stabilizers, destabilizers, and probes, recent assays to identify ligands, and the potential biological applications of these DNA structure-modulating molecules.
... [8] Importantly,b oth drugs contain multiple stereocenters and are administered in enantiopure form.T he active daunorubicin enantiomer binds to right-handed human DNA, whereas its mirror image is inactive and binds selectively to (nonhuman) left-handed DNA. [9] Similar behavior was found for Doxorubicin. [10] As ar esult, both drugs are marketed as single enantiomers.I ti st herefore vital to explore methods to obtain such compounds in enantiopure form.S ince conventional synthesis of chiral compounds will yield racemic mixtures, alternative asymmetric synthetic methods are required. ...
Chiral molecules exhibiting a quinone and/or hydroquinone moiety are ubiquitous in natural products and small molecule drugs. Herein, we describe a chiral quinone‐hydroquinone molecule that racemizes through a reversible redox reaction. Using a combined computational and experimental approach, we show that this racemization proceeds via an intermolecular reaction mechanism. Starting from two achiral reactants, this molecule could be obtained in enantiopure form using Viedma ripening.
... By analogy, Tsuji et al. [308] showed that an optically active helicene-spermine conjugate ( Figure 37 [309] reported that an anticancer agent (+)-dunorubicin and its novel (-)-enantiomer (WP 900) exhibited enantioselectivity in binding to DNA. ...
The four most important and well-studied phenomena of mirror symmetry breaking of molecules were analyzed for the first time in terms of available common features and regularities. Mirror symmetry breaking of the primary origin of biological homochirality requires the involvement of an external chiral inductor (environmental chirality). All reviewed mirror symmetry breaking phenomena were considered from that standpoint. A concept of chiral and racemic fields was highly helpful in this analysis. A chiral gravitational field in combination with a static magnetic field (Earth’s environmental conditions) may be regarded as a hypothetical long-term chiral inductor. Experimental evidences suggest a possible effect of the environmental chiral inductor as a chiral trigger on the mirror symmetry breaking effect. Also, this effect explains a conformational transition of the right-handed double DNA helix to the left-handed double DNA helix (B-Z DNA transition) as possible DNA damage.
