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PubMed1993

Mechanisms of distamycin A/DAPI chromosome staining. I. Competition binding effects of nonintercalative DNA groove-binding agents in situ and in vitro.

The molecular mechanism underlying distamycin A-induced differential DAPI fluorescent staining of metaphase chromosomes was studied in Sus scrofa domestica both cytologically, using, besides DAPI, two isomeric derivatives of DAPI (D288.45 and D288.48), and molecularly, by in vitro competitive-binding studies using S. scrofa satellite DNA and synthetic DNA polymers. Significant differences in heterochromatin staining were observed between D288.45 and D288.48. Distinct distamycin A/DAPI bands were obtained with DAPI and D288.45 but not with D288.48. Circular dichroism measurements were performed to characterize the displacement of DAPI from its DNA binding sites by distamycin A and also netropsin. Distamycin A was most effective in displacing DAPI when DAPI was bound to contiguous clusters of AT base pairs and much less effective in displacing DAPI bound to GC or mixed AT/GC base-pair sequences. The results of these competitive-binding studies provide the basis of a molecular explanation of the quenching phenomenon of distamycin A counterstaining on chromosomal DAPI fluorescence.

Animals↗
PubMed2005

Advances in DNA-ligands with groove binding, intercalating and/or alkylating activity: chemistry, DNA-binding and biology.

It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalating or alkylating activity are described and evaluated for prospective applications. Furthermore there exists DNA minor groove binder with different basic structures which does not possess the typical polyamide chain, including dimeric intercalating chromophores. Finally new results about peptide nucleic acids and related nucleic acid bases linked with polyamides are reported. In pronounced examples the structural chemistry, synthesis, DNA binding with several biophysical methods, molecular aspects, structure activity relationship, topoisomerase inhibition, antitumour and antibacterial effects are discussed in detail.

Alkylating Agents↗
PubMed1995

Inhibition of poly(2'-fluoro-2'-deoxyadenylic acid)-directed-reverse transcriptase activity.

Some intercalating and nonintercalating drugs have been tested as inhibitors on the DNA synthesis reaction catalyzed by avian myeloblastosis virus (AMV) reverse transcriptase, in the presence of polyriboadenylic acid (poly(rA)) and poly(2'-fluoro-2'-deoxyadenylic acid) (poly(dAfl)) as templates. In both cases, the inhibition was higher with the intercalating drug ethidium bromide than with the nonintercalating analog tetramethyl ethidium bromide. Ethidium bromide inhibited more efficiently the poly(rA)- than the poly(dAfl)-directed reverse transcriptase reaction; in the latter case, the inhibition was non-competitive in relation to TTP. On the other hand, the reaction catalyzed in the presence of the 2'-fluorinated polynucleotide as template was inhibited to a higher extent by other nonintercalating drugs, berenil, netropsin, and distamycin. The inhibitions of both reactions by dideoxy TTP, novobiocin and HPA-23 are also discussed.

DNA↗
PubMed1999

Bis-benzimidazole anticancer agents: targeting human tumour helicases.

Certain DNA minor groove binding agents, distamycin, netropsin, and a series of anticancer bis-benzimidazoles can block DNA helicase activity by binding to duplex DNA at specific base sequences. DNA helicases are crucial to cell DNA replication, transcription and repair because these enzymes separate double-stranded DNA, thereby preparing the strands for enzymatic manipulation. From our studies we have developed a hypothesis that focuses on cellular DNA helicase action as a mechanistic site where these minor groove binders can act. A crucial aspect for modulation of DNA activity by drugs is for specificity and selectivity. A series of DNA-interactive bis-benzimidazole analogues of Hoechst 33258 was also prepared to explore the potential for anticancer activity mediated for certain of the drugs via bioreductive activation by endogenous NADH or NADPH. The biological endpoints examined included intracellular distribution in euoxic and hypoxic conditions observed by fluorescence microscopy; relative efficacy as antimetabolites determined by the MTT [tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay in euoxic and hypoxic conditions; and relative inhibitory activities on human DNA helicase, as determined by degree of dissociation of GC B6486 DNA. The intracellular distribution was unique to each of the test compounds. Compounds V-93 and V-153, the respective semiquinone and quinone derivatives, demonstrated the predicted enhanced cytotoxicity and anti-helicase activities, supporting the concept that preferential binding of DNA at 5'-CG and TG sequences provides a novel approach to anticancer drug development.

Animals↗
PubMed1999

Potent antitumor activity of MS-247, a novel DNA minor groove binder, evaluated by an in vitro and in vivo human cancer cell line panel.

We synthesized a novel anticancer agent MS-247 (2-[[N-[1-methyl-2-[5-[N-[4-[N,N-bis(2-chloroethyl) amino] phenyl]] carbamoyl]-1H-benzimidazol-2-yl] pyrrol-4-yl] carbamoyl] ethyldimethylsulfonium di-p-toluenesulfonate) that has a netropsin-like moiety and an alkylating residue in the structure. We evaluated antitumor activity of MS-247 using a human cancer cell line panel coupled with a drug sensitivity database and subsequently using human cancer xenografts. The average MS-247 concentration required for 50% growth inhibition against a panel of 39 cell lines was 0.71 microM. The COMPARE analysis revealed that the differential growth inhibition pattern of MS-247 significantly correlated with those of camptothecin analogues and anthracyclins, indicating that MS-247 and the two drug groups might have similar modes of action. MS-247 exhibited remarkable antitumor activity against various xenografts. A single i.v. injection of MS-247 significantly inhibited the growth of all 17 xenografts tested, which included lung, colon, stomach, breast, and ovarian cancers. In many cases, MS-247 was more efficacious than cisplatin, Adriamycin, 5-fluorouracil, cyclophosphamide, VP-16, and vincristine and was almost comparable with paclitaxel and CPT-11; these are the most clinically promising drugs at present. MS-247 was noticeably more effective than paclitaxel (in HCT-15) and CPT-11 (in A549, HBC-4, and SK-OV-3). The toxicity of MS-247, indicated by body weight loss, was reversible within 10 days after administration. The MS-247 mode of action showed DNA binding activity at the site where Hoechst 33342 bound, inhibited topoisomerases I and II (as expected by the COMPARE analysis) blocked the cell cycle at the G2-M phase, and induced apoptosis. These results indicate that MS-247 is a promising new anticancer drug candidate to be developed further toward clinical trials.

Animals↗
PubMed1999

"DNA clearing" from non-covalently bound agents in mammalian cells as a new mechanism of drug resistance.

Earlier, we have described the process of active dissociation or "DNA clearing" from non-covalently bound agents in living mammalian cells. The vital fluorescent bisbenzimidazole dye Hoechst 33342, which binds DNA in the minor groove tightly but non-covalently, was used for studying the interaction of non-covalently binding agents with DNA. Multiple drug resistance (MDR) in tumour cells is related to the expression of transport proteins that alter the cellular drug transport and distribution. Three different groups of genes (mdr, MRP, and LRP) and their products are implicated in MDR (A. Krishan, C. M. Fitz, and I. Andritsch, Cytometry 29:279-285 (1997)). To obtain new cell lines characterized by enhanced process of active dissociation of non-covalently bound agents from DNA or "DNA clearing", we carried out step-by-step selection with increasing concentrations of Hoechst 33342. The rodent cell lines hyperresistant to Hoechst 33342 and selected from AA8 were named AA8Hoe-R-1-AA8Hoe-R-10, and the cell lines selected from L cells were called LHoe-R-1-LHoe-R-10. The most resistant of them, AA8Hoe-R-6 and AA8Hoe-R-7, were able to grow in the presence of 80 microm/ml of Hoechst 33342 in the cell culture medium. All mutants were analyzed with the flow cytometric technique and were divided into two different groups. We conclude that the drug resistance of the first group of cell lines was due to changes in transport proteins. The second group of the resistant cell lines was characterized by an enhanced dissociation of the bisbenzimidazole dye-DNA complex. As we believe, the enhanced level of "DNA clearing" was caused by the amplification of some genes, because the gradual increase of Hoechst resistance in the same cell line resulted from the increase in the ability to remove the dye from DNA. These lines were shown to be also resistant to netropsin.

Animals↗
PubMed1999

Effect of sulphur crosslinking on the stability and transition of triple helical DNA.

In continuation to our work on order-order and order-disorder transition in triple stranded DNA when it is bounded to netropsin, we report in this communication the stabilizing/destabilizing effect of disulphide linkage on the phase dynamics of the triplex using the amended Zimm-Bragg theory. It is observed that in contrast to the sequential triplex-->duplex -->single strand melting of the uncrosslinked triplex, crosslinking causes the triplex state to melt directly to the single stranded state, with no apparent intermediary of a duplex state. Since there is no overall difference in the enthalpy of crosslinked and uncrosslinked triplexes, the transition is entropy driven.

Base Sequence↗
PubMedDate not supplied

[Structure of the complexes of distamycin type antibiotics and actinomycin D with DNA: new data on the localization of these antibiotics within the DNA narrow groove].

It is shown that antibiotics actinomycin D (AM), netropsin (Nt), distamycin A (DM) and the propyl analogue of distamycin A (pDM) being complexed with DNA are located within the narrow groove of DNA. A comparative investigation of the 3H-dimethyl sulphate methylation extent of free calf thymus DNA and its complexes with AM, Nt, DM and pDM reveals that upon DNA saturation these antibiotics decrease the methylation level of the narrow groove (AM by 30%, pDM by 50%, DM by 65% and Nt by 70%). In the triple complex of DNA+AM+DM the methylation level of the narrow groove drops by 80%. The large groove is not shielded by these antibiotics at all. However, the methylation level of the large groove decreases by 50% for T6 phage DNA due to the presence of glucosyl residues linked to 5-hydroxymethylcytosine within the large groove. The binding of AM to DNA saturated with Nt or with the analogue of distamycin A (DM2) containing the 2 N-methylpyrrole residues has been investigated by spectrophotometry. The apparent number of binding sites for AM in these 2 complexes is about half as much as observed for free DNA while the saturation level of the binding decreased only by about 20%. This proves simultaneous presence of AM and Nt (DM2) within the narrow groove of DNA.

Animals↗
PubMed1990

The interaction of unfused polyaromatic heterocycles with DNA: intercalation, groove-binding and bleomycin amplification.

A number of unfused-aromatic cations have been found to bind to DNA by intercalation and to amplify the bleomycin catalysed cleavage of DNA. These molecules are more similar in structure to unfused minor-groove binding compounds such as netropsin and DAPI than to fused-ring intercalators such as proflavine. An analysis of DAPI interactions with specific sequence DNA polymers has indicated that the binding modes for the molecule are sequence dependent: minor groove binding in sequences of three or more AT base pairs and intercalation in mixed or pure GC base pair sequences. As with other unfused intercalators which bind with their cationic side chains in the major groove, the amidinium groups of DAPI are in the major groove in the GC intercalation complex. DAPI is, thus, a good bleomycin amplifier in GC sequences but its minor-groove binding mode in AT sequences leads to bleomycin inhibition.

Base Sequence↗
PubMed1990

The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure.

We have determined the domains of the mammalian high mobility group (HMG)I chromosomal proteins necessary and sufficient for binding to the narrow minor groove of stretches of A.T-rich DNA. Three highly conserved regions within each of the known HMG-I proteins is closely related to the consensus sequence T-P-K-R-P-R-G-R-P-K-K. A synthetic oligopeptide corresponding to this consensus "binding domain" (BD) sequence specifically binds to substrate DNA in a manner similar to the intact HMG-I proteins. Molecular Corey-Pauling-Koltun model building and computer simulations employing energy minimization programs to predict structure suggest that the consensus BD peptide has a secondary structure similar to the antitumor and antiviral drugs netropsin and distamycin and to the dye Hoechst 33258. In vitro these ligands, which also preferentially bind to A.T-rich DNA, have been demonstrated to effectively compete with both the BD peptide and the HMG-I proteins for DNA binding. The BD peptide also contains novel structural features such as a predicted Asx bend or "hook" at its amino-terminal end and laterally projecting cationic Arg/Lys side chains or "bristles" which may contribute to the binding properties of the HMG-I proteins. The predicted BD peptide structure, which we refer to as the "A.T-hook," represents a previously undescribed DNA-binding motif capable of binding to the minor groove of stretches of A.T base pairs.

Adenine↗
PubMed1991

Binding of antibiotics to DNA.

The DNA molecule can serve as host to numerous guest ligands, some of which are antibiotics, and almost all of which are endowed with anticancer or antimicrobial activity. Many guest ligands are quite large and complex in structure, and an array of intermolecular contacts underlie their complementarity to their macromolecular receptor. Often the process of molecular recognition involves conformational adjustments on the part of the interacting species, but the lion's share of the adjusting is demanded of the DNA helix which commonly ends up considerably distorted. Generally the lock must bend to accommodate the key. Two fundamentally different modes of binding can be identified: intercalation and minor groove-binding. The former mode is exemplified by daunomycin or actinomycin and the latter by netropsin or distamycin. Intercalation is associated with substantial extension and unwinding of the helix whereas groove binding is characterized by replacement of the spine of hydration and by lesser effects on helix geometry such as local bending. Bifunctional (or bis-) intercalation, as seen with echinomycin, causes the most far-reaching perturbations in the structure of DNA. It might even involve altered base pairing, which has been observed in complexes between echinomycin and oligonucleotides but has not yet been detected with macromolecular DNA in solution.

Anti-Bacterial Agents↗
PubMed1988

[Computer aided design of anticancer drugs].

The recent advances in computer science and technology enabled us to use computer for drug-design. Calculation of structural features of drugs and modeling of biomacromolecules by means of 3D-computer graphics afford a new approach to comprehend a molecular interaction which is important for drug action. As target molecules for anticancer drug, DNA structure can be elucidated and drug-DNA complex model can be constructed to give further insight for drug design. For example, complex of DNA double helix and bleomycin was built and by conjunction with other complex model such as mitomycin C, anthramycin, and netropsin it would be able to design a base sequence specific DNA-groove binding molecule. In addition, DNA is also a target molecule for antibiotics which intercalate between base pairs. Rational design of intercalator and groove binder thus would lead a novel anticancer drug. On the other hand, combination of the fruitful results of molecular biology and gene engineering with computer technology, will give a detail of protein structure which is one of most desired information for designing novel drugs.

Antineoplastic Agents↗
PubMed1975

Transmission of stability (telestability) in deoxyribonucleic acid. Physical and enzymatic studies on the duplex block polymer d(C15A15) - d(T15G15).

The properties of the duplex block polymer d(C15A15) - d(T15G15) were examined by thermal denaturation and nuclease susceptibility studies in the absence and presence of drugs (actinomycin and netropsin) which bind specifically to only one end of the block polymer. The nucleotide composition of one region of this synthetic double-helical DNA affected the properties of a contiguous but remote region. Furthermore, the binding of actinomycin influenced the properties of both the binding and nonbinding regions. These findings suggest a mechanism for gene regulation at a distance.

Adenosine Monophosphate↗
PubMed1984

Heritable fragile sites on human chromosomes. XI. Factors affecting expression of fragile sites at 10q25, 16q22, and 17p12.

The fragile sites at 10q25, 16q22, and 17p12 can all be induced in lymphocyte culture by BrdU or BrdC added 6-12 hrs prior to harvest. Without induction, fra(10)(q25) is rarely expressed spontaneously, whereas fra(16)(q22) is frequently expressed spontaneously. Fra(17)(p12) is frequently expressed spontaneously but is probably expressed only after induction in some individuals. Distamycin A, netropsin, and Hoechst 33258 induced high levels of expression of fra(16)(q22) and fra(17)(p12) but did not enhance expression of fra(10)(q25). The mechanisms of induction of fra(16)(q22) by BrdU and distamycin A appear to be different, since the time of induction by BrdU reaches a maximum about 12 hrs prior to harvest whereas induction by distamycin A requires much longer exposure. The fragile sites at 10q25 and 16q22 were both induced in fibroblast culture by BrdU. Fra(17)(p12) is accepted as a fragile site because preliminary studies show that it behaves similarly in lymphocyte culture to fra(16)(q22); however, there is only limited evidence for fragility at 17p12.

Bisbenzimidazole↗
PubMed1995

Synthesis, DNA binding, footprinting and in vitro antitumour studies of a meta-hydroxy analogue of Hoechst 33258.

An analogue of Hoechst 33258, bearing a phenolic hydroxyl group in the meta rather than para position, was designed using molecular graphics to introduce hydrogen-bonding potentials between this OH group and the C = O group of cytosine-9 and the NH2 group of guanine-4', of the opposite strand of the B-DNA duplex, d(CGCGAATTCGCG)2. This derivative (meta-Hoechst) was synthesized in seven steps and characterized. Its binding to DNA was assessed by measurements of melting temperatures (Tm) and found to be similar in strength and AT preference to the parent Hoechst 33258 at this gross level. The AT preference of meta-Hoechst and Hoechst 33258 was probed further using hydroxyl radical footprinting on the tyrT DNA fragment, for which clear footprints were detected at AAT, AAA and ATAT runs, as for netropsin and distamycin. Hydroxyl radical footprinting was carried out on a trimer of CGCGAATTCGCG cloned into a longer DNA fragment, for which clear footprints for both Hoechst 33258 and meta-Hoechst were detected in regions with four or more contiguous AT base pairs. Three cell lines derived from haematological malignancies were more sensitive to both Hoechst 33258 and meta Hoechst than lines derived from solid tumours, but there was no significant difference between the activity of these two Hoechst derivatives.

Animals↗
PubMed1993

Synthesis and DNA binding selectivity of pyrrole-amidine oligopeptides.

A class of DNA binding antibiotics endowed with antiviral and antitumor properties is reviewed. Starting from the original natural products, namely distamycin and netropsin, new compounds have been recently synthesized with the aim to obtain agents with specific affinity for defined DNA sequences and with different interaction mechanism (reversible or irreversible).

Animals↗
PubMed1998

Synthesis, DNA-binding properties and cytotoxic activity of flavin-oligopyrrolecarboxamide and flavin-oligoimidazolecarboxamide conjugates.

The aim of this study was to develop novel series of photosensitizer-DNA minor groove binder hybrids composed of a flavin (isoalloxazine) chromophore linked to a moiety related to netropsin or distamycin. Three series (Fla-Pyr, Fla-Gly-Pyr and Fla-Gly-Im) were synthesized which differ by the number and the nature of the heterocyclic nuclei in the oligopeptide units, the nature of the linker and its anchoring position on the flavin. In terms of DNA binding and DNA specificity, satisfactory data are obtained in the Fla-Pyr and Fla-Gly-Pyr series; in terms of photo-induced cytotoxicity, the results are disappointing. The present study allows us to draw the following structure-activity relationships: (i) substitution of the flavin nucleus in either the N3 or the N10 position does not affect the activity; (ii) tris-pyrrolic hybrids are more efficient than bis- and tetra-pyrrolic analogs; (iii) the presence of a glycin in the linking chain does not suppress the DNA binding properties or the cytotoxic activities of the hybrids; and (iv) the replacement of the pyrrole nuclei by imidazoles has a drastic effect since it results in the loss of DNA affinity and cytotoxicity.

Aminoimidazole Carboxamide↗
PubMedDate not supplied

Ligands recognizing the minor groove of DNA: development and applications.

Polyamide ligands comprised of pyrrole, imidazole and hydroxypyrrole rings have been developed over the past decade which can be used to target many different, predetermined DNA sequences through recognition of functional groups in the minor groove. The design principles for these ligands are described with a description of the characterization of their binding. Variations containing linked recognition modules have been described which allow high affinity and specificity recognition of DNA sequences of over 15 base pairs. Recent applications of these ligands in affecting biological response through competition with proteins for DNA binding sites are reviewed.

Antiviral Agents↗