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PubMed1990

Stimulation by gamma-carboline derivatives (simplified analogues of antitumor ellipticines) of site specific DNA cleavage by calf DNA topoisomerase II.

gamma-Carbolines are tricyclic aromatic compounds which intercalate into DNA base pairs and exhibit significant cytotoxic and antitumor activities. These compounds which are structurally related to ellipticine by deletion of an aromatic ring, induce DNA breaks in cultured L1210 cells. Since the mechanism of cytotoxic activity of ellipticines involves DNA topoisomerase II, this enzyme might also be a target for gamma-Carbolines. We have tested this hypothesis using an in vitro system containing purified enzyme and pBR322 DNA. The ability of nine derivatives to stabilize the DNA-enzyme covalent complex was studied and compared to their cytotoxicity. The four less cytotoxic compounds do not induce cleavable complex to a significant extent. In contrast, the two most cytotoxic gamma-Carbolines are the most efficient stabilizers of the cleavable complex. The last three compounds exhibit an intermediate cytotoxicity and cleavage activity. In the presence of gamma-Carbolines, cleavage occurs predominantly at a single site in pBR322 which is one of the cleavage sites observed with ellipticines. The cleavage position was determined at the nucleotide level. The increased DNA cleavage specificity observed with gamma-Carbolines suggests that a tricyclic system is as efficient as ellipticines for DNA topoisomerase II cleavage at DNA sequences involved specifically in cytotoxic response. The data presented support the hypothesis that DNA topoisomerase II is a target involved in the mechanisms of action of antitumor gamma-Carbolines.

Amsacrine↗
PubMed1991

Clastogenic action of ellipticine over the cell cycle of human lymphocytes and influence of posttreatments with caffeine and ara-C at G2.

The clastogenic potential of the intercalating compound ellipticine, an antitumor alkaloid, has been demonstrated in mammalian cells. To characterize the mechanism of action of this drug over the cell cycle, human lymphocyte cultures from 2 healthy donors were treated with 3 micrograms/ml ellipticine in 30-min pulses during different phases of the cell cycle and analyzed for chromosomal aberrations and sister-chromatid exchanges. The G2 phase was most sensitive in terms of induction of aberrations, followed by S and G1. Chromatid-type aberrations were the most common type of chromosomal damage. Induction of SCEs was significantly high only after treatment at G1, when the frequencies of SCEs doubled. The post-treatment effect of lymphocytes with inhibitors of DNA repair, 10(-3) M caffeine and 5 x 10(-6) M 1-beta-D-arabinofuranosylcytosine, was also tested by adding 3 micrograms/ml ellipticine at G2 in 30-min pulses and immediately followed by caffeine and/or ara-C during the last 3 h before harvesting. Three experiments performed on blood from 3 donors showed a moderate potentiation effect on the frequency of chromatid-type aberrations (about 2-3 times) by both inhibitors. Likewise, a 3-fold increase was observed in the frequencies of chromosomal aberrations when caffeine and ara-C were combined. The present data demonstrate that posttreatment with caffeine and ara-C at G2 can modify the response of human lymphocytes treated with ellipticine by increasing the clastogenic action of this compound or by changing the cell-cycle progression.

Caffeine↗
PubMed1997

Azatoxin is a mechanistic hybrid of the topoisomerase II-targeted anticancer drugs etoposide and ellipticine.

One approach to broadening the diversity of topoisomerase II-targeted anticancer agents is to generate novel compounds by combining structural elements of drugs known to stimulate enzyme-mediated DNA cleavage. The first agent to emerge from such a rational drug design is azatoxin, a hybrid drug that fuses chemical structures from etoposide and ellipticine. Since these drugs differ significantly in their structural and mechanistic attributes, azatoxin may preferentially retain the functional properties of one of these two drugs, behave as a hybrid molecule, or act as a novel pharmacophore. Therefore, the properties of azatoxin were characterized to determine relationships between its mechanism of action and those of its parent compounds. Azatoxin, like etoposide, binds to DNA in a nonintercalative fashion. However, similar to ellipticine, the drug has no effect on enzyme-mediated DNA religation and apparently stimulates scission primarily by enhancing cleavage complex formation. Depending on the species of topoisomerase II examined, the cleavage potency of azatoxin resembles that of either of its chemical parents. Furthermore, out of 43 DNA cleavage sites analyzed, approximately 90% of those induced by azatoxin are shared with either etoposide, ellipticine, or both drugs. Finally, competition studies indicate that azatoxin interacts with topoisomerase II in the enzyme domain utilized by etoposide and ellipticine. Taken together, these results strongly suggest that azatoxin is a mechanistic hybrid of its parent compounds and shares functional properties with both drugs.

Amino Acid Substitution↗
PubMed1994

Design, synthesis, and study of 9-substituted ellipticine and 2-methylellipticinium analogues as potential CNS-selective antitumor agents.

N,N-Dimethylformamide (DMF) dineopentyl acetal-mediated O-alkylations of 9-hydroxyellipticine gave 9-ethoxy-, 9-(1-methylethoxy)-, and 9-(1,1-dimethylethox)ellipticine (3a, 4a, and 5a, respectively). Methylation of the O-alkylellipticines gave the corresponding N-methylpyridinium iodides (3b, 4b, and 5b). The iodides were converted to the acetates (3c, 4c, and 5c) by ion-exchange resin. Attempts to prepare 9-(2,2,2-trifluoroethoxy)ellipticine (6a) using the DMF acetal gave 10-(2,2,2-trifluoroethoxy)-9-hydroxyellipticine (8a). 9-(2,2,2-Trifluoroethoxy)- and 9-phenoxyellipticine (6a and 7a, respectively) were prepared by total synthesis. The ellipticines and N-methylellipticinium derivatives were evaluated for in vitro antitumor activity against a panel of human tumors. 2-Methyl-9-(1,1-dimethylethoxy)ellipticinium acetate (5c) was inactive, but all of the other compounds exhibited significant antitumor activity. The ellipticines showed no significant subpanel specificity; however, the N-methylellipticinium compounds tested did exhibit specificity for the CNS tumor subpanel.

Antineoplastic Agents↗
PubMed1988

Synthesis and antitumor activity of quaternary ellipticine glycosides, a series of novel and highly active antitumor agents.

A series of ellipticine glycosides [2-N-glycosyl quaternary pyridinium salts of three ellipticines: ellipticine (1), 9-methoxyellipticine (2), and 9-hydroxyellipticine (4)] were stereoselectively synthesized in good yields by an improved condensation reaction between ellipticines [1, 2, and 9-acetoxyellipticine (3)] and protected (peracylated and perbenzylated) glycosyl halides with cadmium carbonate, followed by deprotection. These glycosides were preliminarily evaluated for their antitumor activity in the L1210 leukemia system. Twenty-six (53%) of the 49 glycosides tested were curative, and five [9-hydroxyellipticine L-arabinopyranoside (41b), D-lyxofuranoside (43a), L-lyxopyranoside (44b), D-xylofuranoside (49a), and L-rhamnopyranoside (56)] were selected for extended evaluation on the basis of their high levels of activity. The structure-activity relationships are discussed. The selected glycosides showed remarkable activity in six different murine tumor systems with excellent therapeutic ratios; their efficacy surpassed that of doxorubicin against three of these systems. On the basis of these results and ease of formulation, the two glycosides 41b (SUN4599) and 49a (SUN5073) were selected for further preclinical evaluation and possible clinical development.

Alkaloids↗
PubMed1996

Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates.

Three ellipticine-estradiol conjugates were synthesized in an effort to target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extending from the 17 alpha position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C-9 (compound 5) positions of ellipticine. The ellipticine-estradiol conjugates were evaluated for their abilities to bind to estrogen receptors, to inhibit topoisomerase II, and for their cytotoxicities in human cancer cell lines. Conjugates 3 and 5 displayed weak binding affinities of 0.132 and 0.303 for the estrogen receptor (relative to estradiol = 100), while conjugate 4 did not show any detectable binding to the estrogen receptor. Compound 3 was a moderate inhibitor of topoisomerase II (IC50 24.1 microM), while 4 and 5 were inactive. Conjugate 3 was consistently more cytotoxic (GI50 values 1-10 microM) than compounds 4 and 5 (GI50 values 10-100 microM) in a variety of human cancer cell lines. None of the compounds displayed any selectivity for estrogen-receptor positive cell lines, which probably reflects their weak affinities for estrogen receptors.

Antineoplastic Agents↗
PubMed2005

Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1.

To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI-National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations-indicative of MDR1-mediated resistance-were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Binding characteristics of 4-S proteins from rat and mouse liver. High affinity of ellipticines.

The binding characteristics of 4-S components (carcinogen-binding protein) from livers of Sprague-Dawley rats, C57BL/6 and DBA/2 mice have been examined before and after separation from other binding components presents in the cytosol. Competitive potency of 3-methylcholanthrene, benzo[alpha]pyrene, beta-naphthoflavone and 20 ellipticines, a series of compounds differently substituted on the dimethyl-pyrido-carbazole nucleus and deprived of carcinogenic activity, has been determined with [3H]3-methylcholanthrene and/or [3H]benzo[a]pyrene as radioligands. The inducing ability of the same compounds for aryl hydrocarbon hydroxylase and for ethoxyresorufin-O-deethylase has been compared to their affinity for the 4-S protein and the Ah receptor respectively. The main results of this study are as follows. 1. The intrinsic binding characteristics of 4-S proteins were dependent on both the nature of the radioligand used and the presence or absence of other cytosolic binding components. 2. The heterocyclic ellipticines were revealed as strong ligands for the carcinogen-binding protein (stronger than benzo[alpha]pyrene for five derivatives substituted in the A ring of ellipticine), with IC50 values ranging from 0.047 microM (8-hydroxyellipticine) to 5.8 microM (N2-ethyl-9-hydroxyellipticinium). 3. When the affinity of ellipticines was plotted versus their inducing ability of aryl hydrocarbon hydroxylase and ethoxyresorufin-O-deethylase, it appears that a good correlation exists for the Ah receptor but not for the 4-S protein. It is concluded that these data, as well as the lack of enzymatic induction after benzo[alpha]pyrene treatment of DBA/2 mice, which display a high level of 4-S protein, do not support the implication of this binding component in the positive control of cytochrome P-450 induction.

Alkaloids↗
PubMed1992

Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives: structure-activity relationship.

Ellipticines are aromatic compounds that intercalate between DNA base pairs and display significant antitumor activity. The cytotoxicity of these compounds is mediated by DNA topoisomerase II, and the presence of a hydroxy group at position 9 of the pyridocarbazole ring system of ellipticines has been found to be essential for high levels of cytotoxicity. The ability of 13 ellipticine derivatives to stabilize the topoisomerase II-DNA covalent complex in vitro was studied, and the data obtained with five pairs of hydroxylated and nonhydroxylated analogues indicate that the hydroxy group at position 9 plays a crucial role in the stabilization of the complex. The influence, upon the complex stabilization, of various substituents at positions 1, 2, 5, and 6 of the pyridocarbazole ring system was investigated. The interaction with DNA of four ellipticine derivatives was studied in the topoisomerase II standard medium. Results suggest that the degree of unwinding might be a determinant of topoisomerase II-DNA-drug complex stability. In addition, the 5-ethyl derivative was observed to induce covalent complex stabilization by a cooperative mechanism.

DNA Damage↗
PubMed1992

DNA-binding properties of a distamycin-ellipticine hybrid molecule.

We have synthesized a distamycin-ellipticine hybrid compound and investigated its interaction with DNA, using various optical and gel electrophoresis techniques. Binding of the hybrid to DNA is evidenced by spectral shifts, fluorescence quenching, and induced linear dichroism. Absorbance measurements have been used to generate Scatchard plots, which reveal that the interaction cannot be described adequately in terms of a single binding mode, probably because of simultaneous intercalation and minor groove binding of the ligand. Competition with added distamycin has been used to verify involvement of the N-methyl-pyrrole portion of the hybrid molecule in the binding reaction. From electric linear dichroism experiments, it is estimated that the orientation of the DNA-bound ellipticine chromophore in the hybrid differs by about 10 degrees from the orientation of the equivalent chromophore lacking a distamycin tail. Topoisomerase assays establish that binding of the hybrid unwinds the DNA helix by a minimum of 11 degrees, which is consistent with intercalation but notably smaller than the unwinding angle of ellipticine. In footprinting experiments, it is found that the AT- and GC-specificity of distamycin and ellipticine, respectively, appear to be merged in the binding of the hybrid, which produces a pattern of protection distinct from the characteristic patterns for either of the parent compounds. The hybrid is an extremely effective inhibitor of cutting by DNase I.

Chelating Agents↗
PubMed1985

Ellipticines: correlation between in vitro DNA intercalation and physiological properties?

The in vitro DNA-intercalator ellipticine and five of its derivatives have been investigated for some of their physiological effects on several Escherichia coli strains. The highly water-soluble, quaternarized derivatives of ellipticine have no bactericidal effect and do not induce the synthesis of rec A protein. Ellipticine itself, as well as the derivatives obtained by adding an amino or an hydroxyl substituent in position 9, promotes the induction of rec A protein and is cytostatic on some bacterial strains. The non-intercalating brominated derivative is a strong bactericidal agent, which apparently promotes the lysis of the bacteria. At low concentrations, it slightly induces the synthesis of rec A protein. We conclude that there is no correlation at all between the physiological properties of the ellipticines and their physico-chemical behavior in vitro.

Alkaloids↗
PubMed1983

Mutagenicity and cytotoxicity of five antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella.

The mutagenicity and cytotoxicity of five antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay and in six strains of Salmonella. All five compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine, and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay in the presence or absence of Aroclor 1254-induced rat liver S9, and all except the last compound were mutagenic in Salmonella. Based on the reversion pattern obtained in various frame-shift and DNA repair-proficient (uvrB+) or -deficient (uvrB) strains of Salmonella in the presence or absence of S9, the first three compounds appear to cause frame-shift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. However, 9-aminoellipticine intercalates only weakly and may instead exert its mutagenic activity primarily (or exclusively) by forming a covalent adduct with DNA. Compared to the published antitumor data obtained in mice, the results in Salmonella and Chinese hamster ovary cells suggest that the ability of ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine to intercalate with DNA, induce frame-shift mutations, and cause cell killing is associated with and may be the basis for their antitumor activity. The observation that the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.

Alkaloids↗
PubMed1981

Ellipticine, 9-hydroxyellipticine, and 9-hydroxyellipiticinum: some biochemical properties of possible pharmacologic significance.

Ellipticine, 5,11-dimethyl-(6H)-pyrido-(4,3,b)-carbazole (NSC 71795) is a potent cytotoxic and antitumor agent. Several of its derivatives share these properties and nine hydroxylated compounds are even more potent. 2-Methyl-9-hydorxyellipticinium (NSC 264-137) has thus recently been shown to display some therapeutic effectiveness in human breast cancers. The biochemical mechanism of this action is discussed in this paper. DNA has been implied as the target of ellipticine and some derivatives; however, these drugs do not break DNA in cultured L1210 cells. Moreover, several other biochemical constituents are able to bind these compounds in vitro as efficiently as DNA. In this paper the interactions between ellipticine and some of those derivatives and (a) ascitic phospholipids monolayers and (b) cytochrome P450 microsomal proteins are studied and discussed. Finally, the hypothesis that the nonhydroxylated ellipticine derivatives might be better cytotoxic agents because they can be oxidized and generate free radical species through a monovalent electron transfer process is presented. This hypothesis is supported by experiments carried out on the oxidation of 9-hydroxyellipticine and 2-methyl-9-hydroxyellipticine by peroxidases.

Alkaloids↗
PubMed1978

Characterization of ellipticine binding to native calf thymus DNA.

The binding of [14C]ellipticine to native calf thymus DNA was studied using equilibrium dialysis. A Scatchard polt revealed the presence of high-and low-affinity binding sites in DNA, the former having a K of 4.0 X 10(7) M(-1) and an n (saturation limiting of binding) of 0.078 (1mol ellipticine/13 mol of DNA nucleotides). The forces involved in stabilizing the high-affinity binding, which has been equated with intercalative binding, were due to a combination of hydrophobic interactions and hydrogen bonding. Difference spectra of ellipticine in the presence of the polydeoxynucleotides, poly d(A-T) or poly d(G-C), showed that there was no base specificity involved in the high-affinity binding. Ellipticine binding to the low-affinity sites, which has been equated with surface binding, was due primarily to the participation of electrostatic interactions of ellipticine with the anionic phosphate groups on the double helical surface of DNA.

Animals↗
PubMed1992

Binding of benzo(a)pyrene, ellipticine, and cis-parinaric acid to beta-lactoglobulin: influence of protein modifications.

The binding of benzo(a)pyrene, ellipticine, and cis-parinaric acid to native, esterified, and alkylated beta-lactoglobulin was followed by enhancement of the ligand fluorescence. Three studied ligands bind to native or modified beta-lactoglobulin in apparent molar ratios varying between 1/8 and 2/1, with apparent dissociation constants in the range of 10(-8) M for ligand/beta-lactoglobulin complexes. The studied, chemically modified beta-lactoglobulin derivatives display higher binding affinities for all studied ligands, cis-parinaric acid excluded. The reductive alkylation of epsilon-NH2 lysyl residues of beta-lactoglobulin increases the apparent molar ratios of benzo(a)pyrene and cis-parinaric acid, and decreases it for ellipticine. The esterified and native beta-lactoglobulin complexed to the investigated ligands display similar stoichiometries. Dynamic light scattering study of ligand-beta-lactoglobulin complexes in solution shows the formation of aggregates: the apparent hydrodynamic radius value of beta-lactoglobulin dimer (3.4 nm) reaches 49, 46, and 74 nm upon addition and binding of benzo(a)pyrene, ellipticine, and cis-parinaric acid, respectively.

Alkylation↗
PubMed1988

Effects of verapamil on the cellular accumulations and toxicity of several antitumor drugs in 9-hydroxy-ellipticine-resistant cells.

9-OH-Ellipticine (9-OH-E)-resistant cells are not only resistant to the DNA topoisomerase II inhibitors, but also to some other antitumor agents, such as actinomycin D (AD), adriamycin (ADM), daunorubicin and vincristine. It was previously shown that a decreased uptake accounts for the cross-resistance of these cells to AD and ADM which then suggested that the 9-OH-E-resistant cells might display some of the properties usually associated with the multidrug resistance phenotype. In this work, we have examined the effects of verapamil, a drug which is known to overcome the multidrug resistance, on the toxicity and the cellular accumulation of four cytotoxic agents: 9-OH-E, 2N-methyl-9-hydroxy-ellipticinium (NMHE), AD and ADM, either on 9-OH-E resistant cells or on a multidrug resistant subline derived from the same sensitive parental cells. Verapamil inhibited the cellular accumulation of the ellipticine derivatives in the sensitive DC-3F cells, and the toxicity of these drugs on these cells was correspondingly decreased. On either one of the resistant cell lines, verapamil had no effect on the toxicity and the cellular accumulation of 9-OH-E. In contrast, in the presence of verapamil, the cellular accumulation of NMHE by the 9-OH-E and the multidrug resistant cells was about 50% and 300% increased, respectively. The increased NMHE cellular concentration in the multidrug resistant cells was associated with an 8-fold increased toxicity. The major structural characteristics which might account for this difference between the sensitivities of both ellipticine derivatives to the effects of verapamil on the multidrug resistant cells is the presence of a positive charge on the nitrogen in position 2 of the 6H-pyridocarbazole molecule. Finally, verapamil circumvented partially the cross-resistance of DC-3F/9-OH-E cells to AD and ADM by increasing the accumulation of these drugs inside the cells.

Alkaloids↗
PubMed1989

Interaction of ellipticine and an indolo[2,3b]-quinoxaline derivative with DNA and synthetic polynucleotides.

The non-covalent DNA interaction of the anticancer drug ellipticine (Scheme I, 1a) as well as an indolo[2,3-b]-quinoxaline derivative (Scheme I, 3b) with a dimethylaminoethyl side chain has been studied by light absorption, linear dichroism (LD) and fluorescence. Compound 3b (Scheme I) has antitumorigenic as well as antiviral activity. Both compounds bind to DNA or synthetic polynucleotides such as poly(dA-dT).(dA-dT) and poly(dG-dC).(dG-dC) by intercalation. In contrast to ellipticine, compound 3b (Scheme I) exhibits a significant binding specificity for alternating AT sequences. Its fluorescence is strongly enhanced in AT sequences and quenched in GC sequences. Fluorescence titrations evaluated as Scatchard plots show that both ellipticine and compound 3b (Scheme I) bind to the nucleic acids according to a non-cooperative neighbor exclusion model.

Alkaloids↗
PubMed1976

PMR studies of the self-association of DNA intercalating ellipticine derivatives in aqueous solution.

In aqueous solution DNA intercalating ellipticine derivatives aggregate in n-mers. The self-association constants K are higher than those of 2-methoxy-6-chloro-9-[3-dimethylaminopropyl-amino]-acridine and ethidium bromide. They are of the same order as that of actinomycin D but inferior to that of acridine orange. The increase of the 9-hydroxy-ellipticine constant by addition of sodium chloride shows the importance of anion participation in the mechanism of stacking in accordance with the high energy of self-association. In the stacked n-mers the ellipticine rings are inverted. The geometry shows the importance of the orientation of the quadrupole axis in the intermolecular association of the intercalating drugs.

Alkaloids↗