The effect of ionic strength on DNA-tigand unwinding angles for acridine and quinoline derivatives

Jones, Robert L.; Lanier, A C; Keel, Rebecca A.; Wilson, W. David

doi:10.1093/nar/8.7.1613

Cited by 87 publications

(51 citation statements)

References 17 publications

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“…In one of the most important studies [9] it was shown that (i) the planar (aromatic) system of rings C and D ( Figure 1) is involved in an intercalative interaction with the duplex DNA whereas rings A and B protrude out of the helix interior into the minor groove where they interact with the minor-groove and/or top1 functionalities and (ii) all four protoberberines (1-4) depicted in Figure 3 unwind the B-DNA by approximately 11°due to the partial intercalative binding; this helix unwinding angle is in excellent agreement with the 10°value reported earlier by other inevestigators for the DNA binding of berberine, a structurally similar protoberberine to those studied here ( Figure 3) [23,24]. Recently, computer modeling techniques have also been employed to study the intercalative binding of some protoberberines with a d(ApT) 2 minihelix, but no correlation between the binding energy and the top1 poisoning activity was observed [9,10], indicating that the interaction of the drug with top1 residues makes a significant contribution to the stability of the ternary drug -DNA -top1 cleavable complex.…”

Section: Introductionsupporting

confidence: 89%

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Kettmann

Kostálová

Höltje

2004

J Comput Aided Mol Des

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Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the -1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

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Section: Introductionsupporting

confidence: 89%

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Kettmann

Kostálová

Höltje

2004

J Comput Aided Mol Des

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“…A maximum attainable value of 260 is provided by ethidium (27) and some related phenanthridines (40). Lower unwinding angles such as reported for acridines, (41,42), adriamycin, 120 (43) or daunorubicin, 100 (25) (25) also using sonicated calf thymus DNA and other similar experimental techniques analyzed the DNA viscosity enhancement of several planar aromatic molecules. They found that daunorubicin and 9-methoxyellipticine gave the expected increase in viscosity corresponding to the theoretical helix extension of 3.4 A per bound drug molecule.…”

Section: Discussionmentioning

confidence: 82%

Is the bithiazole moiety of bleomycin a classical intercalator?

Hénichart¹,

Bernier²,

Helbecque³

et al. 1985

Nucl Acids Res

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Bleomycin is a widespread anticancerous drug, the biological activity of which having been extensively studied. Its metal ion-chelating portion has been shown to cleave DNA whereas the role of the bithiazole moiety is still questionable. In order to elucidate this problem some 2',4-disubstituted bithiazoles structurally related to the "tripeptide S" moiety of bleomycin were synthesized and their interaction with DNA was studied using 4Tm, fluorescence, EPR and viscometry techniques. The results of ATm and fluorescence quenching determinations were in favour of a binding of the bithiazole part by an intercalation process. Nevertheless, the use of the spin-label probes indicated only a partial intercalation of the ring between the base-pairs. Moreover, viscometry data which clearly exhibited a slight decrease of DNA length in the presence of bithiazole derivative led to the proposal of a binding model involving a partial insertion of a thiazole ring which wedges in between the bases at a bending point of DNA.

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“…We have shown that Acr(CH2)50H, the acridine derivative used to synthesize (Tp)n(CH2)5Acr, gives rise to the same spectroscopic behavior as quinacrine, even though the binding constants with DNA and synthetic polynucleotide duplexes are lower because of the lack of a positive charge on the substituent that is linked to the 9-amino group (our unpublished results). Quinacrine is known to intercalate between DNA base pairs and to unwind DNA by =17° (15).…”

Section: Resultsmentioning

confidence: 99%

Nucleic acid-binding molecules with high affinity and base sequence specificity: intercalating agents covalently linked to oligodeoxynucleotides.

Asseline¹,

Delarue²,

Lancelot³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

181

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Oligodeoxyribonucleotides covalently linked to an intercalating agent via a polymethylene linker were synthesized. Oligothymidylates attached to an acridine dye (Acr) through the 3'-phosphate group [(Tp),(CH2)mAcr] specifically interact with the complementary sequence. The interaction is strongly stabilized by the intercalating agent. By using absorption and fluorescence spectroscopies, it is shown that complex formation between (Tp),(CH2)mAcr and poly(rA) involves the formation of n A-T base pairs, where n is the number of thy. mines in the oligonucleotide. The acridme ring intercalates between ANT base pairs. Fluorescence excitation spectra reveal the existence of two environments for the acridine ring, whose relative contributions depend on the linker length (m). The binding of (Tp)4(CH2)mAcr to poly(rA) is analyzed in terms of site binding and cooperative interactions between oligonucleotides along the polynucleotide lattice. Thermodynamic parameters show that the covalent attachment of the acridine ring strongly stabilizes the binding of the oligonucleotide to its complementary sequence. The stabilization depends on the linker length; the compound with m = 5 gives a more stable complex than that with m = 3. These results open the way to the synthesis of a family of molecules exhibiting both high-affinity and high-specificity for a nucleic acid base sequence.Molecules with high affinity and base-sequence specificity are required to control gene expression at different levels. Several possibilities may be contemplated depending on whether double-stranded or single-stranded nucleic acids are chosen as targets. For example, the regulation of transcription involves proteins that recognize specific duplex DNA sequences in both prokaryotes and eukaryotes (1, 2). However, there is no general rule yet established that could allow us to build an oligopeptide sequence aimed at recognizing a given base or base pair sequence (3). Moreover, the amino acid side chains that are involved in contacts with base or base pairs are not contiguous in the polypeptide chain.The most obvious candidate to allow for the specific recognition of a nucleic acid fragment is an oligonucleotide with the complementary sequence, provided the nucleic acid bases in the target sequence have their hydrogen bonding sites available. This is obviously so if the target nucleic acid region exists as a single-stranded structure. This might also be true in a duplex structure if a sufficient supplementary energy of interaction were provided either by modifying the oligonucleotide (see below) or by imposing constraints on the duplex structure (e.g., in superhelical DNA or upon binding of melting proteins). Also it must be kept in mind that important regulatory regions in transcription and replication must be transiently opened as observed-e.g., in the complex formed by bacterial RNA polymerase with a promoter (the so-called "open complex") (4) or at the replication fork (5). Actively transcribed genes in eukaryotes also possess regions upstream f...

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The effect of ionic strength on DNA-tigand unwinding angles for acridine and quinoline derivatives

Cited by 87 publications

References 17 publications

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Is the bithiazole moiety of bleomycin a classical intercalator?

Nucleic acid-binding molecules with high affinity and base sequence specificity: intercalating agents covalently linked to oligodeoxynucleotides.

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