Specific interactions of distamycin A and its analogs with (A-T) rich and (G-C) rich duplex regions of DNA and deoxypolynucleotides

Luck, G.; Zimmer, Christoph; Reinert, Karl-Ernst; Arcamone, Frederico

doi:10.1093/nar/4.8.2655

Cited by 106 publications

(57 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results also confirm that DAPI binds preferentially to A.T-rich DNA (19 (8,9). It binds along the minor groove of the DNA double helix, interacting with both strands of the duplex (8,10). The results found using Nycodenz gradients are in agreement with the expected binding of netropsin to A.T base pair clusters (8).…”

Section: And Discussionsupporting

confidence: 79%

Effect of ligand binding on the buoyant density of DNA in Nycodenz gradients

Ford¹,

Rickwood²

1984

Nucl Acids Res

View full text Add to dashboard Cite

The effect of ligand binding upon the buoyant density of DNA in Nycodenz gradients has been studied using DNAs of differing base compositions. The effect of both intercalating ligands (ethidium bromide and proflavin) and non-intercalating ligands (distamycin A, DAPI and netropsin) has been studied. The binding of intercalating ligands to DNA has essentially no effect on the buoyant density of DNA in Nycodenz gradients. The nonintercalating ligands were found to increase the buoyant density of DNA in a base specific manner. The increase in buoyant density can be interpreted in terms of disruption of the hydration shell of the DNA molecule caused by the binding of the ligand along the minor groove of the DNA helix.

show abstract

Section: And Discussionsupporting

confidence: 79%

Effect of ligand binding on the buoyant density of DNA in Nycodenz gradients

Ford¹,

Rickwood²

1984

Nucl Acids Res

View full text Add to dashboard Cite

show abstract

“…The interpretation of these data was that the spermidine inhibition is specific for duplex DNA because of its unique structure. Distamycin A, a DNA minor-groove binder that has an affinity for A+T-rich sites (32), also inhibited guanine methylation in a dose-dependent manner (31). This (34), and it does show some preference for A+T-rich sequences.…”

Section: Resultsmentioning

confidence: 93%

Inhibition of N-methyl-N-nitrosourea-induced mutagenicity and DNA methylation by ellagic acid.

Dixit¹,

Gold²

1986

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

View full text Add to dashboard Cite

Ellagic acid, a naturally occurring plant phenol, inhibits the activity of the direct-acting mutagen N-methyl-N-nitrosourea (MeNU) in Salmonella typhimurium TA100.Ellagic acid at 0.10, 0.25, 0.50, and 1.00 mM inhibited the mutagenicity of MeNU (0.40 mM) by 3%, 13%, 45%, and 60%, respectively. Ellagic acid (3 mM) also inhibited the mutagenic activity of in the presence of pyrazole-induced rat liver fraction S-9. The effect of ellagic acid on DNA methylation was studied by incubating 0, 0.72, 1.32, 2.64, and 6.60 mM ellagic acid with DNA (0.9 mM nucleotide) and PHJMeNU (0.66 mM). HPLC analysis of DNA hydrolysates showed that ellagic acid caused a dose-dependent 36-84% decrease in 06-methylguanine but only a 20% decrease in the 7-methylguanine adduct. Under conditions where methylation at the 06 position of guanine in double-stranded DNA was inhibited 65% by ellagic acid, no significant inhibition of either 06-or 7-methylguanine formation was detected in single-stranded DNA. Affinity-binding studies revealed that [3H]eilagic acid binds equally to doublestranded or single-stranded DNA but that poly(dA dT) binds 1.5 times as much ellagic acid as does poly(dG-dC). The binding of ellagic acid to DNA is dependent on the concentration of both ellagic acid and DNA. The specific inhibition of 06. methylguanine formation only in double-stranded DNA and the relatively low inhibition of 7-methylguanine formation rule out the possibility that ellagic acid prevents DNA alkylation by scavenging the electrophilic intermediate generated in the hydrolysis of MeNU. The results suggest that ellagic acid inhibition of MeNU-induced mutagenicity is due to specific inhibition of methylation at the 06 position of guanine through an ellagic acid-duplex DNA afflnity-binding mechanism.Ellagic acid (2,3,7,8-tetrahydroxy[J]benzopyrano [5,4,3-cde][J]benzopyran-5,10-dione), a natural product shikimate derivative present in soft fruits and vegetables (1-3), inhibits the carcinogenicity of benzo[a]pyrene (B[a]P) (4) and the carcinogenicity and mutagenicity (5-8) and DNA binding (9, 10) of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), an activated form of B[a]P. It was suggested that the chemopreventive activity of ellagic acid results from its ability to accelerate the detoxification of BPDE by forming a BPDE-ellagic acid adduct (11). It was further suggested that the reason for the rapid reaction between BPDE and ellagic acid resulted from an initial ir-7r nonbonded interaction. The apparent second-order rate constant for the disappearance of BPDE at pH 7.0 is more than 300-fold faster in the presence of ellagic acid (11). In summary, the proposed antimutagenic and antitumorigenic activity of ellagic acid was suggested to result from its direct interception of the "ultimate" electrophilic form of B[a]P, thereby preventing DNA adduction.While this mechanism may be effective with the reactive electrophiles generated in the metabolism of polycyclic aromatic hydrocarbons, it is not likely that such a "scavenging" mechanism would be eff...

show abstract

“…If the natural distamycin molecule is designated as Dst-3 (for its three pyrrole rings), synthetic analogues with as few as two or as many as seven pyrroles can be prepared. Comparative studies have been made of binding preferences of netropsin and Dst-2 through Dst-5 (23,(32)(33)(34). Although netropsin and Dst-2 apparently demand 4-base-pair sites containing only ART base pairs, the longer distamycin analogues become increasingly tolerant of occasional isolated G-C base pairs, particularly near the ends of a binding site.…”

mentioning

confidence: 99%

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Kopka¹,

Yoon²,

Goodsell³

et al. 1985

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

800

577

View full text Add to dashboard Cite

X-ray analysis of the complex of netropsin with the B-DNA dodecamer of sequence C-G-C-G-A-A-T-TBrC-G-C-G reveals that the antitumor antibiotic binds within the minor groove by displacing the water molecules of the spine of hydration. Netropsin amide NH furnish hydrogen bonds to bridge DNA adenine N-3 and thymine 0-2 atoms occurring on adjacent base pairs and opposite helix strands, exactly as with the spine of hydration. The narrowness of the groove forces the netropsin molecule to sit symmetrically in the center, with its two pyrrole rings slightly non-coplanar so that each ring is parallel to the walls of its respective region of the groove. Drug binding neither unwinds nor elongates the double helix, but it does force open the minor groove by 0.5-2.0 A, and it bends back the helix axis by 8°across the region of attachment. The netropsin molecule has an intrinsic twist that favors insertion into the minor groove of B-DNA, and it is given a small additional twist upon binding. The base specificity that makes netropsin bind preferentially to runs of four or more ACT base pairs is provided not by hydrogen bonding but by close van der Waals contacts between adenine C-2 hydrogens and CH groups on the pyrrole rings of the drug molecule. Substitution of one or more pyrroles by imidazole could permit recognition of G'C base pairs as well, and it could lead to a class of synthetic "lexitropsins," capable of reading any desired short sequence of DNA base pairs.Netropsin and its close relative distamycin ( Fig. 1) are antiviral antitumor antibiotics that, although too toxic for clinical use, have received extensive study as the paradigms of base-specific yet non-intercalative DNA-binding drug molecules. First isolated from Streptomyces netropsis in 1951 (1, 2), netropsin exerts its biological activity by binding tightly to double-helical B-DNA, interfering with both replication and transcription (3, 4). It shows little or no affinity for single-stranded DNA or RNA or for double-stranded RNA or DNA-RNA hybrids (3-5), suggesting that it does not bind to the A helix. It also fails to bind to left-handed Z-DNA; in fact, binding of netropsin to DNA favors A-to-B and Z-to-B helix transitions (6, 7).Chemical protection studies (3,4,8) and Overhauser NMR experiments (9) indicate that netropsin does not intercalate between base pairs, but it binds within the minor groove of the intact double helix, using hydrogen bonds between netropsin amide NH and exposed adenine N-3 and thymine 0-2 on the floor of the minor groove. The drug molecule attaches to clusters of four or more A'T or ITC, but not to G-C, base pairs (3, 10, 11). Alternating A-T-A-T regions bind netropsin less well than continuous runs of A or T (12, 13). Binding involves both an electrostatic component from the two cationic ends and hydrogen bonds from the central three amide NH groups, although neither aspect is absolute- FIG. 1. The netropsin molecule can be regarded as being assembled from (left to right): guanidinium, amide, methylpyrrole, amide, methylpyrr...

show abstract

Specific interactions of distamycin A and its analogs with (A-T) rich and (G-C) rich duplex regions of DNA and deoxypolynucleotides

Cited by 106 publications

References 23 publications

Effect of ligand binding on the buoyant density of DNA in Nycodenz gradients

Effect of ligand binding on the buoyant density of DNA in Nycodenz gradients

Inhibition of N-methyl-N-nitrosourea-induced mutagenicity and DNA methylation by ellagic acid.

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Contact Info

Product

Resources

About