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PubMed1988

Structural modeling of the distamycin A-d(CGCGAATTCGCG)2 complex using 2D NMR and molecular mechanics.

The structure of the distamycin A-d(CGCGAATTCGCG)2 complex has been determined through a combination of SKEWSKY and NOESY 2D NMR experiments and molecular mechanics calculations. NMR data provided upper bounds on many proton-proton pairs. The advantage of the SKEWSKY/NOESY method is that small groups of strongly coupled spins can be treated accurately as isolated systems. The AMBER molecular mechanics package, modified to include the NMR constraints, was used in energy refinements. Distamycin A fits snugly into the 5'-AATT-3' minor-groove binding site. Structural analysis revealed van der Waals contacts between A5, A6, and A18 C2H and drug H3 protons, potential three-center hydrogen bonding between drug amide protons and adenine N3 and thymine O2 atoms analogous to the spine of hydration in the crystal structure of the free DNA, and stacking of the sugar O1' atoms of A6-C21, T7-T20, and, T8-T19, over drug pyrrole rings 1, 2, and 3, respectively. In addition to hydrophobic effects, hydrogen bonding, and electrostatic interactions proposed by others, it is suggested that stacking interactions between DNA sugar O1' atoms and the three drug pyrrole rings contribute to the stability of the complex.

Base Composition↗

PubMed1990

DNase I susceptibility of bent DNA and its alteration by ditercalinium and distamycin.

The bending of kinetoplast DNA from Crithidia fasciculata is thought to be related to the periodic distribution of AA or TT cluster sequences. The sensitivity to DNase I of the two strands of this DNA was analyzed at nucleotide resolution by sequencing gel electrophoresis. The effect on the DNase I cleavage pattern of two drugs, ditercalinium and distamycin, that are able to remove bending was analyzed. The same analysis was done on a pBR 322 DNA fragment of random sequence as a control. The periodic distribution of the AA or TT clusters in the bent DNA fragment was first analyzed by computing the autocorrelation function of the AA or TT clusters in the bent DNA fragment. It is shown that the AT tracts are on average 10.5 base pairs apart. This value is almost identical with that of the B-DNA helix pitch in solution [10.5 (Wang, 1979); 10.6 +/- 0.1 (Rhodes & Klug, 1980)]. To reveal the periodic pattern of DNase I cleavage on this bent DNA, alone or in presence of drugs, the cross correlation between the different bands obtained from DNAse I cleavage and the presence of AA or TT sequences was computed. This shows that GC and mixed sequences are the most sensitive regions. These data also suggest that there is a periodic fluctuation in the width of the minor groove in the bent fragment. Ditercalinium and distamycin alter the DNase I cutting pattern of the bent DNA fragment but in an inverse fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1980

Interaction of netropsin and distamycin with deoxyribonucleic acid: electric dichroism study.

We report dichroism and equilibrium binding studies of netropsin (Net) and distamycin A3 (Dist) binding to deoxyribonucleic acid (DNA). We show that at low degrees of binding (r) to calf thymus DNA, Net induces a considerable increase in the apparent DNA length (14 A/drug molecule bound), closely analogous to the results reported earlier for Dist. In addition, we show that chicken erythrocyte DNA shows length changes similar to those of calf thymus DNA upon distamycin binding. DNA length reaches a maximum at 1 bound drug/20-30 base pairs and then decreases to its initial value by r = 0.1. This effect is not seen for two other DNAs with nearly identical A + T base pair content and may therefore arise from the details of base sequence or base modification in eukaryotic DNA. We also show that Dist binding to calf thymus DNA at low r values is positively cooperative and shows a DNA affinity which is primarily nonionic. We demonstrate that independent of the DNA to which they are bound, the Net and Dist transition moments are inclined by 43 +/- 3 degrees from the helix axis, consistent with the idea that both drugs bind inside and parallel to the DNA small groove. From dichroism measurements, we show that the conformational change induced in calf thymus DNA by Dist does not kink or bend the helix and does not substantially alter the average inclination of the bases. Finally, we outline a statistical mechanical theory for calculation of binding isotherms when binding is coupled to a DNA structural change.

Animals↗

PubMed1995

Synthesis of two distamycin analogues and their binding mode to d(CGCAAATTTGCG)2 in the 2:1 solution complexes as determined by two-dimensional 1H-NMR.

In the course of a study aimed at the synthesis of pyrrole amidine carboxamide DNA-binding agents as novel pharmacological agents, a series of carbamoyl analogues of distamycin, containing an increasing number of pyrrole units, have been obtained by total synthesis. The interaction of the tetrapyrrole carbamoyl 4 with the dodecamer d(CGCAAATTTGCG)2 in comparison with that of the corresponding formylamino analogue 3 has been examined by high-resolution 1H-NMR and molecular modeling. Either ligand binds to DNA in one-drug and symmetric two-drug modes at low drug:DNA ratios, while at high ratios only the two-drug complex was observed. In this article, the structure of 2:1 drugs DNA complexes has been studied by NMR and molecular modeling, which indicate that the two analogues bind the DNA in a similar fashion, in the minor groove of the 5'-AATTT region. In both complexes the two drugs are symmetrically placed along the complementary strands of DNA with the pyrrole ring of one molecule in close contact with those of the other one. Although another region of five consecutive A-T base pairs is available, no evidence of sliding of drug molecules between different binding sites, as in the case of the 2:1 complex of distamycin with the same dodecamer, is observed, thus indicating that increasing the number of N-methylpyrrolecarboxamide units from three to four cases a lengthening of the recognition sequence.

Base Sequence↗

PubMed1993

In vitro cytotoxicity of GC sequence directed alkylating agents related to distamycin.

Imidazole containing analogues 7, 10, and 17 of distamycin wherein the C-terminus contain a dimethylamino moiety have been shown to selectively bind to the minor groove of GC-rich sequences. Accordingly, these agents were employed as vectors for the delivery of a variety of alkylating agents to GC-rich sequences. The alkylating agents are attached to the N-terminus of these vectors thus providing the benzoyl N-mustards (8, 15, and 18 that contain one, two, and three imidazole units, respectively) and substituted acetamides 11-14. Results from the ethidium displacement assay for the formamides 7, 10, and 17 and mustards 15 and 18 showed that these agents bind to calf thymus DNA, poly(dA.dT), poly(dG.dC), and also to coliphage T4 DNA, thus confirming their binding in the minor groove. The reduced binding constants of these compounds for poly(dA.dT) while still binding as strongly, or more strongly, to poly(dG.dC) than distamycin provided evidence for their acceptance of GC sequences. Selectivity for GC-rich sequences was also indicated by CD titration studies. Titration of 10, 15, 17, and 18 to poly(dA.dT) produced weak drug-induced CD bands at approximately 330 nm; however, interaction of these agents to poly(dG.dC) in equimolar drug concentrations gave strong bands in this region. Results from dialysis and cross-link gel experiments provided evidence of alkylation and cross-linking of DNA by the mustards which could explain their enhanced cytotoxicity over the formamido analogues. The bifunctional N-mustard-containing analogues 15 and 18 are significantly more cytotoxic than the monoalkylating acetamides 11-14. The mustards also exhibited significant activity against cell lines derived from solid tumors such as melanomas, ovarian cancers, CNS cancers, and small cell lung cancer.

Alkylating Agents↗

PubMed1989

Novel linked antiviral and antitumor agents related to netropsin and distamycin: synthesis and biological evaluation.

A group of oligopeptides have been synthesized which are structurally related to the natural antiviral antitumor antibiotics netropsin and distamycin bearing two such moieties linked by polymethylene bridges. Cytostatic activity against both human and murine tumor cell lines and their in vitro activity against a range of viruses are reported. Enhanced antiviral activity was obtained against vaccinia virus. As a result of the introduction of the polymethylene linkers [( CH2)n, with n = 1, 2, and 6-8], both the antitumor and antivaccinia virus activity was markedly enhanced, relative to that of the parent compounds netropsin and distamycin. The biological activity of these agents is discussed both in terms of their structural differences and in relation to their minor groove binding to duplex DNA.

Animals↗

PubMed2000

Synthesis and antitumor activity of new benzoheterocyclic derivatives of distamycin A.

The design, synthesis, and in vivo and in vitro antileukemic activity of a novel series of compounds (13-22 and 34), in which different benzoheterocyclic rings, bearing a nitrogen mustard or a benzoyl nitrogen mustard or an alpha-bromoacryloyl group as alkylating moieties, are tethered to a distamycin frame, are reported, and structure-activity relationships are discussed. The new derivatives were prepared by coupling nitrogen mustard-substituted, benzoyl nitrogen mustard-substituted, or alpha-bromoacryloyl-substituted benzoheterocyclic carboxylic acids 23-32 with desformyldistamycin (33) or in one case with its two-pyrrole analogue 35. With very few exceptions, the activities of compounds bearing the same alkylating moiety are slightly affected by the kind of the heteroatom present on the benzoheterocyclic ring. All novel compounds, with one exception, showed in vitro activity against L1210 murine leukemia cell line comparable to or better than that of tallimustine. The compounds in which the nitrogen mustard and the alpha-bromoacryloyl moieties are directly linked to benzoheterocyclic ring showed potent cytotoxic activities (IC(50) ranging from 2 to 14 nM), while benzoyl nitrogen mustard derivatives of benzoheterocycles showed reduced cytotoxic activities, and one compound (16) of this cluster was the sole derivative devoid of significant activity. Compound 18, a 5-nitrogen mustard N-methylindole derivative of distamycin, showed the best antileukemic activity in vivo, with a very long survival time (%T/C = 457), significantly increased in comparison to tallimustine (%T/C = 133), and was selected for further extensive evaluation. Arrested polymerase chain reaction and direct DNA fragmentation assays were performed for compound 18 and the structurally related compounds 13-17 and 19. The results obtained have shown that both alkylating groups and oligopeptide frames play a crucial role in the sequence selectivity of these compounds.

Acrylamides↗

PubMed2003

Synthesis of isochrysohermidin-distamycin hybrids.

The synthesis of the alkylating subunit of the DNA cross-linking agent, isochrysohermidin (2), and its subsequent incorporation into conjugates with distamycin A (1) are described. The DNA binding properties of these agents were compared to that of distamycin A, using a fluorescence intercalator displacement (FID) assay.

Algorithms↗

PubMed1994

Binding of two distamycin A molecules in the minor groove of an alternating B-DNA duplex.

Here we report the 1.8A X-ray structure of a 2:1 drug-DNA complex between distamycin A and an alternating B-DNA octamer duplex d(ICICICIC)2. The two distamycin A molecules are bound side by side with dyad symmetry in an antiparallel orientation in the expanded minor groove. The amides of each drug molecule are hydrogen bonded to the minor groove base atoms of only one DNA strand. The complex not only shows binding of two drug molecules, but the DNA duplex also exhibits striking low-high alternations in the helical twist angles, the sugar puckering and the phosphate conformations, providing the basis for a new model for an alternating B-DNA with a dinucleotide repeat.

Base Sequence↗

PubMed2006

Synthesis of distamycin A polyamides targeting G-quadruplex DNA.

A number of amide-linked oligopyrroles based on distamycin molecules have been synthesized by solid-state methods, and their interactions with a human intramolecular G-quadruplex have been measured by a melting procedure. Several of these molecules show an enhanced ratio of quadruplex vs. duplex DNA binding compared to distamycin itself, including one with a 2,5-disubstituted pyrrole group. Quadruplex affinity increases with the number of pyrrole groups, and it is suggested that this is consistent with a mixed groove/G-quartet stacking binding mode.

DNA↗

PubMed2002

Two 1 : 1 binding modes for distamycin in the minor groove of d(GGCCAATTGG).

Single-crystal X-ray structure determinations of the complex between the minor-groove binder distamycin and d(GGCCAATTGG) reveal two 1 : 1 binding modes which differ in the orientation of the drug molecule in the minor groove. The two crystals were grown from different crystallization conditions and found to diffract to 2.38 and 1.85 A, respectively. The structures were refined to completion using SHELXL-93, resulting in a residual R factor of 20.30% for the 2.38-A resolution structure (including 46 water molecules) and 19.74% for the 1.85-A resolution structure (including 74 water molecules). In both orientations, bifurcated hydrogen bonds are formed between the amide nitrogen atoms of the drug and AT base pairs. With a binding site of at least five base pairs, close contacts between the terminal distamycin atoms and guanine amino groups are inevitable. The detailed nature of several of these interactions was further investigated by ab initio quantum chemical methods.

Adenine↗

PubMed1990

Structure and dynamics of distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at low drug:DNA ratios.

Two-dimensional NMR has been used to study the interaction of distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at low and intermediate drug:DNA ratios (less than 2.0). Drug-DNA contacts were identified by nuclear Overhauser effect spectroscopy, which also served to monitor exchange of the drug between different binding sites. At low drug:DNA ratios (0.5), distamycin A binds in two orientations within the five central A-T base pairs and has a preference (2.2:1) for binding with the formyl end directed toward the 5' side of the A-rich strand. The pattern of drug-DNA contacts corresponding to the preferred binding orientation are consistent with the drug sliding between adjacent AAAT and AATT binding sites at a rate that is fast on the NMR time scale. Similarly, the pattern of NOEs associated with the less favored orientation are consistent with the drug sliding between adjacent AATT and ATTT sites, again in fast exchange. Off-rates for the drug from the major and minor binding orientations were measured to be 2.4 +/- 1.5 and 3.3 +/- 1.5 s-1, respectively, at 35 degrees C. At intermediate drug:DNA ratios (1.3) exchange of the drug between the two one-drug and the two sites of a two-drug complex is observed. Off-rates for both drugs from the 2:1 complex were measured to be 1.0 +/- 0.5 s-1 (35 degrees C).

Base Sequence↗

PubMed2000

[2,1-c][1,4]benzodiazepine (PBD)-distamycin hybrid inhibits DNA binding to transcription factor Sp1.

We designed and synthesized the hybrid 6, prepared combining the minor groove binders distamycin A and pyrrolo [2,1-c][1,4] benzodiazepine (PBD) 4, related to the natural occurring anthramycin (2) and DC-81 (3). In this paper, the effects of the compound 6 on molecular interactions between DNA and transcription factor Sp1 were studied. The results obtained demonstrate that PBD-distamycin hybrid is a powerful inhibitor of Sp1/DNA interactions.

Animals↗

PubMed2000

Shape-selective binding of geometrically-constrained bis-distamycins to a DNA duplex and a model Okazaki fragment of identical sequence.

The binding of ligands to nucleic acids is of great interest for the control of gene expression and other nucleic acid mediated processes. We have evaluated the binding of several geometrically-constrained bis-distamycins to a model Okazaki fragment [OKA], or a DNA duplex having identical base sequence [DD], using gel-shift assays, optical spectroscopy and differential scanning calorimetry. In the case of covalent attachment of two distamycins to a central benzene ring, a similar binding profile was observed for [DD] as was observed for [OKA] (para binds [K(app) > 10(6) M(-1)], meta binds only weakly). For a central pyridyl ring, however, clear distinction between the binding to [DD] and binding to [OKA] was observed. While none of the three meta isomers having a central pyridyl ring bound [OKA], two of them (MT-17 and MT-12) bound [DD] [K(app) > 10(6) M(-1)]. These results demonstrate subtle differences in lexitropsin shape and placement of electronegative atoms may result in selective binding to a nucleic acid duplex based both on base sequence and chemical composition. Selective binding to DNA duplexes may be useful for designing ligands that regulate transcription, but do not interfere in other nucleic acid mediated processes.

Base Sequence↗

PubMed1974

Conformation dependent binding of netropsin and distamycin to DNA and DNA model polymers.

The binding of the antibiotics netropsin and distamycin A to DNA has been studied by thermal melting, CD and sedimentation analysis. Netropsin binds strongly at antibiotic/nucleotide ratios up to at least 0.05. CD spectra obtained using DNA model polymers reveal that netropsin binds tightly to poly (dA) . poly (dT), poly (dA-dT) . poly(dA-dT) and poly (dI-dC) . poly (dI-dC) but poorly, if at all, to poly (dG) . poly (dC). Binding curves obtained with calf thymus DNA reveal one netropsin-binding site per 6.0 nucleotides (K(a)=2.9 . 10(5) M(-1)); corresponding values for distamycin A are one site per 6.1 nucleotides with K(a)= 11.6 . 10(5) M(-1). Binding sites apparently involve predominantly A.T-rich sequences whose specific conformation determines their high affinity for the two antibiotics. It is suggested that the binding is stabilized primarily by hydrogen bonding and electrostatic interactions probably in the narrow groove of the DNA helix, but without intercalation. Any local structural deformation of the helix does not involve unwinding greater than approximately 3 degrees per bound antibiotic molecule.

Animals↗

PubMed1991

Detection of an unusual distortion in A-tract DNA using KMnO4: effect of temperature and distamycin on the altered conformation.

The chemical probes potassium permanganate (KMnO4) and diethylpyrocarbonate (DEPC) can be used to study the conformational flexibility of short tracts of adenine (A-tracts) present in DNA. With these probes, we demonstrate that a novel distortion is induced in a 5 base pair A-tract at low temperature. Formation of this distorted A-tract structure, which occurs in a DNA fragment from the promoter region of the plasmid pBR322, is distinguished by a dramatic increase in the KMnO4 reactivity of the central thymines in this tract at 12 degrees C. This alteration occurs in the absence of any detectable rearrangement in the conformation of the adenines in the complementary strand. Induction of this low temperature A-tract structure is blocked by the minor groove binding drug distamycin. Hydroxyl radical footprinting of distamycin binding to the fragment containing the d(A)5 tract at 12 degrees C suggests that this drug has two different modes of binding to DNA in agreement with recent NMR data. These experiments show that short A-tracts are capable of forming more than one structural variant of B DNA in solution. The possible relationship between the intrinsic bending of DNA containing short phased A-tracts and the low temperature A-tract conformation is discussed.

Adenine↗

PubMed1991

Interactions of nucleic acids with distamycins. Binding of Dst-3 to d(CGTTTAAACG)2 and d(CGTACGTACG)2.

The binding between Distamycin 3 and the palindromic duplexes d(CGTTTAAACG)2 and d(CGTACGTACG)2 was investigated by two independent techniques: UV-Vis absorption in the Job's plot approach and Induced Circular Dichroism. Both decamers bind two molecules of peptide per duplex, with close overall affinities. This result indicates that a row of six A:T base pairs can accommodate two molecules of drug and that the minimal binding site of Distamycin 3 can consist of just two A:T base pairs.

Base Sequence↗

PubMed1997

The sequence specificity of alkylation for a series of benzoic acid mustard and imidazole-containing distamycin analogues: the importance of local sequence conformation.

The covalent sequence specificity of a series of nitrogen mustard and imidazole-containing analogues of distamycin was determined using modified sequencing techniques. The analogues tether benzoic acid mustard (BAM) and possess either one, two or three imidazole units. Examination of the alkylation specificity revealed that BAM produced guanine-N7 lesions in a pattern similar to conventional nitrogen mustards. The monoimidazole-BAM conjugate also produced guanine-N7 alkylation in a similar pattern to BAM, but at a 100-fold lower dose. The diimidazole and triimidazole conjugates did not produce detectable guanine-N7 alkylation but only alkylated at selected sites in the minor groove. Unexpectedly, the alkylation specificity at equivalent doses was nearly identical to that found for the previously reported pyrrole-BAM conjugates. The consensus sequence, 5'-TTTTGPuwas strongly alkylated by the triimidazole conjugate in preference to other similar sites including three occurrences of 5'-TTTTAA. Footprinting studies were carried out to examine the non-covalent DNA binding interactions. These studies revealed that the tripyrrole- BAM conjugate bound non-covalently to the same AT-rich sites as distamycin. In contrast, whereas the Im3lexitropsin bound non-covalently to GC-rich sequences, the triimidazole-BAM conjugate did not detectably footprint to either GC- or AT-rich regions at equivalent doses. The results indicate that the alkylation event is not solely dictated by the non-covalent binding and might be influenced by a unique sequence dependent conformational feature of the consensus sequence 5'-TTTTGPu.

Alkylation↗