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At least 19 recordsLinked to original sources
PubMed1989

Sequence-specific intercalating agents: intercalation at specific sequences on duplex DNA via major groove recognition by oligonucleotide-intercalator conjugates.

An acridine derivative was covalently linked to the 5' end of a homopyrimidine oligonucleotide. Specific binding to a homopurine-homopyrimidine sequence of duplex DNA was demonstrated by spectroscopic studies (absorption and fluorescence) and by "footprinting" experiments with a copper phenanthroline chelate used as an artificial nuclease. A hypochromism and a red shift of the acridine absorption were observed. Triple-helix formation was also accompanied by a hypochromism in the ultraviolet range. The fluorescence of the acridine ring was quenched by a stacking interaction with a G.C base pair adjacent to the homopurine-homopyrimidine target sequence. The intercalating agent strongly stabilized the complex formed by the oligopyrimidine with its target duplex sequence. Cytosine methylation further increased the stability of the complexes. Footprinting studies revealed that the oligopyrimidine binds in a parallel orientation with respect to the homopurine-containing strand of the duplex. The intercalated acridine extended by 2 base pairs the region of the duplex protected by the oligopyrimidine against degradation by the nuclease activity of the copper phenanthroline chelate. Random intercalation of the acridine ring was lost due to the repulsive effect of the negatively charged oligonucleotide tail. Intercalation occurred only at those double-stranded sequences where the homopyrimidine oligonucleotide recognized the major groove of duplex DNA.

Base Sequence↗
PubMed1978

Mechanisms of selectivity of intercalating agents.

Intercalation, insertion of a conjugated polycyclic aromatic ligand between stacked bases of helical DNA, is a common means of binding for a number of agents. This mode of binding generally accounts directly for a number of effects which are broadly uniform for most cells under appropriate conditions. Intercalating agents bind to plasma and intracellular membranes and interact with phospholipids to varying degrees. Biotransformation and activation may also occur at the membrane sites. Besides effects attributable to DNA binding, many of the therapeutic and cytotoxic effects that are characteristic of these agents may be a function of binding and activation in membranes, appearing to be independent of intercalation in some cases but also enhancing DNA-related actions in others. The range of differential effects of intercalating drugs stemming from binding at DNA and membranal sites seems sufficiently diverse to explain selectivity which is expressed in cell- and organ-specific changes, individual and species variability, and numerous drug actions apparently unrelated to intercalation alone.

Animals↗
PubMed1989

Control of gene expression by oligonucleotides covalently linked to intercalating agents.

Oligodeoxynucleotides covalently linked to intercalating agents selectively recognize the complementary sequence of the oligonucleotide. The intercalating agent provides an additional binding energy which stabilizes the complex. These substances can be used in vitro to block mRNA translation. In cell cultures they are able to inhibit the cytopathic effect of viruses, such as influenza virus and the oncogenic virus SV40. They kill trypanosomes in culture as a result of protein synthesis inhibition. A reactive group can be attached to an oligodeoxynucleotide in order to achieve site-directed modifications of the target sequence. Metal complexes of EDTA, phenanthroline or porphyrins induce cleavage reactions of the phosphodiester backbone in both DNA and RNA. Photoactive groups can be used to modify bases in the complementary sequence. The double helix can be recognized and modified by oligonucleotides that bind to the major groove, forming a local triple helix. These site-directed modifications may inhibit biological processes. The oligonucleotide can be made resistant to nuclease digestion by substituting the synthetic alpha-anomers of nucleosides to the natural beta-nucleosides. These results provide the basis for the design of gene-specific inhibitors that can be used as tools in molecular and cellular biology. They also suggest new approaches for the rational development of selective anti-viral, anti-parasitic, and anti-tumoral agents.

Antineoplastic Agents↗
PubMed1988

Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins.

We have investigated the biochemical basis for the hypersensitivity to intercalating agents and epipodophyllotoxins of a Chinese hamster cell mutant, ADR-1. More topoisomerase II-induced DNA strand breaks are accumulated by ADR-1 than by parental CHO-K1 cells following exposure to the intercalating agent amsacrine. Levels of induced DNA strand breaks correlate with cell killing. Topoisomerase II activity is elevated in ADR-1 cells as a consequence of an increased cellular level of topoisomerase II protein. We have studied the phenotype of cell hybrids generated by fusing parental and mutant cells. The hybrid ADR-1/CHO-K1 exhibits normal levels of resistance to amsacrine and expresses the lower, parental level of topoisomerase II. These results provide additional evidence that topoisomerase II mediates the cytotoxic action of intercalating agents and epipodophyllotoxins and suggest that the intracellular level of topoisomerase II is an important determinant of cellular sensitivity to these drugs. This has implications for antitumor therapy. ADR-1 cells provide a model system for studying the effects of topoisomerase II overproduction on cell proliferation and chromosome organization.

Amsacrine↗
PubMed1990

Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II.

A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants. Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents. Despite very low in vitro cytotoxicities, several of the compounds had moderate levels of in vivo antileukemic effects. However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.

Animals↗
PubMed1987

Enzymatic amplification of translation inhibition of rabbit beta-globin mRNA mediated by anti-messenger oligodeoxynucleotides covalently linked to intercalating agents.

The effects of anti-messenger oligodeoxynucleotides, covalently linked to an intercalating agent, on translation of rabbit beta-globin mRNA, were investigated both in wheat germ extract and in microinjected Xenopus oocytes. A specific inhibition of beta-globin synthesis was observed in both expression systems with a modified 11-mer covalently linked to an acridine derivative. In injected oocytes a more efficient block was observed with this modified oligonucleotide than with its unsubstituted homolog. This was ascribed to stacking interactions of the intercalating agent with base pairs which provide an additional stabilization of the [mRNA/DNA] hybrid. We demonstrated that in wheat germ extract, the modified and unmodified oligonucleotides behaved similarly due to the presence of a high RNaseH activity. RNaseH was also present, although to a lesser extent, in the oocyte cytoplasm. This anti-messenger DNA-induced degradation of target mRNA resulted in amplified efficiency of hybrid-arrested translation. This additional mechanism might provide anti-sense DNAs with an advantage over anti-sense RNAs.

Aminacrine↗
PubMed1988

A new combination of two intercalating agents (mitoxantrone + daunomycin) in adult refractory acute leukemia: the DON protocol.

A combination of two intercalating agents, mitoxantrone and daunorubicin with vincristine (the DON regimen) was studied in 16 patients with refractory acute leukemia, including three patients with myeloblastic transformation of refractory anemia with excess of myeloblasts after the failure of first-line chemotherapy and one additional patient with AML relapsing while off therapy. All patients had been heavily pretreated prior to receiving the DON regimen, and all but two had previously received high-dose anthracyclines. Of the 17 patients, nine (53%) who achieved complete remissions (CR) had myeloblastic leukemia. The three patients with acute lymphocytic leukemia did not achieve CR. Cardiac toxicity occurred in two patients and contributed to death in one. These results in very poor risk leukemia suggest a possible synergism in the action of the two intercalating agents and absence of increased cardiotoxicity.

Adolescent↗
PubMed1987

Double helices with parallel strands are formed by nuclease-resistant oligo-[alpha]-deoxynucleotides and oligo-[alpha]-deoxynucleotides covalently linked to an intercalating agent with complementary oligo-[beta]-deoxynucleotides.

Oligo-[alpha]-thymidylates have been synthesized and covalently linked to an intercalating agent (an acridine derivative) and/or to a p-azidophenacyl group. These molecules bind to a complementary oligo-[beta]-deoxynucleotide. A strong stabilization is obtained by covalent attachment of the acridine derivative at the 5' end of the oligo-[alpha]-deoxynucleotide. Upon excitation of the p-azidophenacyl group with ultraviolet light, the oligo-[alpha]-thymidylate is crosslinked to its target sequence. These crosslinks are converted to chain breaks under alkaline conditions. This allows an unambiguous assignment of the orientation of the two oligonucleotide chains. As expected, beta-beta hybrids have an antiparallel orientation, whereas the two chains of alpha-beta hybrids are parallel independently of whether an intercalating agent is covalently linked to the alpha-oligo-nucleotide. Oligo-[alpha]-thymidylates covalently linked to an acridine derivative are highly resistant to endo- and exonucleases. Therefore, they could be used as anti-messengers to block mRNA translation in vivo under conditions where oligo-[beta]-deoxynucleotides are usually hydrolysed.

Exonucleases↗
PubMed1986

Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents.

The reaction of cis-diamminedichloroplatinum(II) and several synthetic or natural double-stranded polydeoxyribonucleotides has been carried out in the presence of such intercalating agents as ethidium bromide, proflavine, and acridine. After incubation of the reaction mixtures at 37 degrees C for 24 hr, some ethidium or proflavine, but no acridine, molecules are tightly bound to nucleic acids. Tight binding is defined by resistance to extraction with butanol, assayed by filtration at acid pH or by thin-layer chromatography at basic pH. In the ternary complexes, there is about one tightly bound ethidium (or proflavine) per platinum residue. At 37 degrees C, but not at 4 degrees C, tightly bound ethidium exchanges with free ethidium, whereas platinum residues do not exchange. The binding and the release of tightly bound ethidium are very slow (several hours). It is suggested that in the ternary complexes, nucleic acid-cis-Pt(NH3)2-intercalating agent, a bidentate adduct (guanine-ethidium or -proflavine)-cis-Pt(NH3)2, is formed. No tightly bound ethidium or proflavine is found when cis-diamminedichloroplatinum(II) is replaced by trans-diamminedichloroplatinum(II). Competition experiments between cis-diamminedichloroplatinum(II), poly(dG-dC), and poly(dG)-poly(dC) or poly(dA-dT) show that the presence of ethidium bromide, proflavine, or acridine interferes with the distribution of platinum between the polynucleotides. These results might help to explain the synergism for drugs used in combination with cis-diamminedichloroplatinum(II) and in the design of new chemotherapeutic agents.

Acridines↗
PubMed1991

Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro.

A new approach to antitumor analog selection was evaluated using in vitro cytotoxicity assays in tumor cells and heart cells. Eight anthracycline antibiotics and five non-anthracycline DNA intercalating agents were separately exposed to human 8226 myeloma cells and neonatal rat heart myocytes in vitro. Survival was measured after six days of culture by the MTT dye method for tumor cells and by ATP content for heart cells. Inhibitory drug concentrations in 50% of cells (IC50) were determined from log-linear dose-response curves for each agent. The IC50 values in the tumor cells ranged from 0.002 micrograms/ml for idarubicin to 3.5 micrograms/ml for the primary metabolite of doxorubicin, doxorubicinol. In contrast, IC50 values for anthracyclines in rat heart cells averaged approximately 357-fold higher than in the tumor cells. The heart cell/tumor IC50 ratio was 114.4 for the parent anthracycline doxorubicin. Compounds with poor cytotoxic selectivity for tumor cells included doxorubicinol, amonafide, amsacrine and bisantrene. Compounds with reduced cardiotoxicity included the anthracyclines daunorubicin (IC50 ratio of 550), esorubicin (IC50 ratio of 1500) and the anthracene derivative mitoxantrone (IC50 ratio of 500). These results show that simultaneous comparisons of cytotoxicity in heart cells and tumor cells can identify agents such as daunorubicin and mitoxantrone which are known to produce less cardiac toxicity in vivo. With further testing, this methodology may be applicable to preclinical screening programs to select active DNA intercalating agents with low cardiotoxic potential.

Adenosine Triphosphate↗
PubMedDate not supplied

Oligodeoxynucleotides covalently linked to intercalating agents: a new class of gene regulatory substances.

Oligodeoxynucleotides have been covalently linked to a 9-aminoacridine derivative via their 3'-phosphate group. Specific complexes are formed with the complementary sequence of the oligonucleotide. The stability is strongly increased due to intercalation of the acridine derivative. Absorption, fluorescence, nuclear magnetic resonance and circular dichroism have been used to characterize complex formation. The stability of the complexes depends on the length of the linker between the acridine derivative and the 3'-phosphate group of the oligonucleotide. Oligonucleotides covalently linked to an intercalating agent can be used to selectively control gene expression. Transcription initiation can be blocked when such an oligonucleotide binds to the transcribed strand in the open complex formed by E. coli RNA polymerase with the bla promoter. With some oligonucleotides, non-specific effects on transcription can be detected, most probably due to binding of the modified oligonucleotide to RNA polymerase. Translation of the messenger RNA from gene 32 of phage T4 can be prevented by using an oligonucleotide complementary to the sequence upstream from the Shine-Dalgarno sequence. Inhibition of translation does not occur in the absence of the intercalating agent covalently linked to the oligonucleotide nor with oligonucleotides which do not have a target sequence on the mRNA.

DNA-Directed RNA Polymerases↗
PubMed1989

alpha-DNA X: alpha and beta tetrathymidilates covalently linked to oxazolopyridocarbazolium (OPC): comparative stabilization of oligo beta-[dT]:oligo beta-[dA] and oligo alpha-[dT]:oligo beta-[dA] duplexes by the intercalating agent.

The influence of the intercalating oxazolopyridocarbazolium (HOPC) on the stabilization of modified oligonucleotides: alpha-T4c5OPC or beta-T4c5OPC associated to beta-oligo (dA) was studied. It appears that the situation is different from what has been observed for the interaction of these modified oligonucleotides with poly (rA). The higher free energy of formation of the alpha-T4c5OPC :beta-oligo(dA), when compared to beta-T4c5OPC, is essentially due to the overall stability added to this system by the intercalator. This enhanced stability comes from a higher number of binding sites of HOPC for the alpha:beta duplex together with a lower van't Hoff energy of formation of the alpha:beta duplex.

Carbazoles↗
PubMed1992

Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents.

A series of substituted dibenzo[1,4]dioxin-1-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[1,4]dioxin-1-carboxylic acids were prepared by a variety of methods. No regiospecific syntheses were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[1,4]dioxin-1-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structure-activity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo[1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase II alpha. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the topo II beta isozyme.

Animals↗
PubMed1990

Embryotoxicity of the intercalating agents m-AMSA and o-AMSA and the epipodophyllotoxin VP-16 in postimplantation rat embryos in vitro.

The intercalating agent, m-AMSA, and the epipodophyllotoxin, VP-16, both topoisomerase II-reactive anticancer agents, are also embryotoxic agents in rat embryos cultured in vitro. Quantifying the embryotoxic effects of these drugs revealed that the no observed adverse effect level (NOAEL) for m-AMSA is 10 nM, the embryotoxic concentration range is 50-500 nM, and complete lethality is observed at 1 microM. In contrast, the NOAEL for o-AMSA, an inactive isomer of m-AMSA, is 1.0 microM, the embryotoxic concentration range is 10-100 microM, and complete lethality occurs at 200 microM. Based upon the concentrations of drugs required to produce 50% embryotoxicity or 50% malformed embryos, m-AMSA exhibits a 200-500-fold-higher embryotoxicity compared to o-AMSA. VP-16 exhibits a NOAEL of 1.0 microM, an embryotoxic concentration range of 2-5 microM, and complete lethality at 10 microM. Compared to m-AMSA, VP-16 is approximately 10-fold less embryotoxic. At appropriate concentrations, all three drugs were dysmorphogenic resulting in embryos that were characterized by hypoplasia of the prosencephalon with associated microopthalmia and dilation of the rhombencephalon. and dilation of the rhombencephalon. As a prelude to future studies focusing on the mechanism of drug-induced embryotoxicity, we have used established biochemical and immunologic methods to identify and quantify topoisomerase II in rat embryos. In addition, we have demonstrated that the embryo topoisomerase II can be inhibited by both m-AMSA and VP-16. Finally, we have used a human cDNA probe to detect topoisomerase II mRNA in the rat embryo. Thus, the combination of the in vitro whole embryo culture and these biochemical/molecular assays should allow us to explore the role of a specific nuclear target, i.e., topoisomerase II, in the teratogenic effects of some commonly employed chemotherapeutic agents.

Abnormalities, Drug-Induced↗
PubMed1986

Cross-resistance to intercalating agents in an epipodophyllotoxin-resistant Chinese hamster ovary cell line: evidence for a common intracellular target.

Several intercalating agents, as well as the epipodophyllotoxins, appear to effect DNA damage through their interaction with type II DNA topoisomerases. However, the relationship of this phenomenon to anti-tumor activity remains unproven. Our studies with an epipodophyllotoxin-resistant cell line not only provide additional evidence that the enzyme is a multidrug target but also serve to implicate it as a mediator of cytotoxic effect. When compared to wild-type cells, the epipodophyllotoxin-resistant Chinese hamster ovary cell line, VpmR-5, exhibits cross-resistance to both the cytotoxic and DNA cleavage activities of 4',9-acridinylaminomethanesulfon-m-anisidide, mitoxantrone, and Adriamycin. Steady-state concentrations of radiolabeled-4',9-acridinylaminomethanesulfon-m-anisidide and daunomycin are identical in both cell lines. Sharp plateaus in the VpmR-5 dose-response curves for Adriamycin-induced DNA strand breaks and cytotoxicity appear to be related to interference with type II topoisomerase-mediated cleavage of DNA at high concentrations of the intercalator. These data support a direct role for DNA strand scission in cell death and also suggest that multidrug resistance may be acquired by a qualitative change in type II topoisomerase that alters interaction of drug with the enzyme or enzyme-DNA complex.

Aminoacridines↗
PubMed1990

Synthesis and biological activity of the intercalating agent 3-acetamido-5-[123/125I]iodo-6-aminoacridine.

3-Acetamido-5-iodo-6-aminoacridine (3), a derivative of the known intercalating agent proflavine (3,6-diaminoacridine) (1) was synthesized, and no-carrier-added 123I and 125I labeled compounds prepared. Compound 3 was taken up by live cells and localized in the nucleus. The intracellular concentration of [125I]3 was 7-fold greater in human prostate carcinoma (PC-3) cells than in normal Chinese hamster lung fibroblast (V-79) cells.

Acridines↗
PubMed1987

Potential antitumor agents. 53. Synthesis, DNA binding properties, and biological activity of perimidines designed as "minimal" DNA-intercalating agents.

A series of compounds based on perimidine have been synthesized and evaluated for their DNA-binding properties and antitumor activity. The fused tricyclic permidine chromophore appears to be the minimal structural requirement for intercalative binding to DNA since the mode of binding could be dictated by the position of attachment of the side chain. The intercalating compounds have DNA association constants (log K = 5.8-6.5) and cytotoxic potencies (IC50 = 500-1500 nM) comparable to those shown by other classes of linear, tricyclic DNA-intercalating antitumor agents (acridinecarboxamides, phenazinecarboxamides), but none of the compounds showed in vivo activity.

Antineoplastic Agents↗
PubMed1985

Chromosomol DNA fragments from mouse cells exposed to an intercalating agent contain a 175-kdalton terminal polypeptide.

A 175 kdalton (kDa) polypeptide is bound covalently to the chromosomal DNA fragments from mouse cells exposed to the intercalating agent 4'-[(9-acridinyl)-amino]methansulphon-m-anisidide. Electron microscopy shows a terminal protein on the DNA fragments, whose 5'-termini are blocked. Since the relative molecular mass of topoisomerase II polypeptide chains is also about 175 kDa and topoisomerase II inhibitors prevent intercalator-induced DNA fragmentation, we propose that the polypeptide bound covalently to the 5'-terminus of the DNA fragments is a polypeptide derived from frequently integrated topoisomerase II operating to normalize torsional stress resulting from intercalation.

Aminoacridines↗