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PubMed1992

N-methylcarbamate derivatives of ellipticine and olivacine with cytotoxic activity against four human lung cancer cell lines.

A series of analogues of the antitumor alkaloids ellipticine and olivacine were tested for cytotoxicity against four human lung cancer cell lines: H69, N417, H460, and H358. Adriamycin (doxorubicin), ellipticine, olivacine, and celiptinium were used as standards. Adriamycin was cytotoxic at 2 microM and celiptinium was inactive at the highest concentrations tested (IC50 > 48 microM). N-methylcarbamates of 9-methoxy-6H-pyrido[4,3-b]carbazole 1-,5-, and 11-methanols gave IC50 values ranging from 0.02 to 0.11 microM against N417, H460, and H358 and were only slightly less effective against H69.

Animals↗
PubMed1988

A new series of ellipticine derivatives (1-(alkylamino)-9-methoxyellipticine). Synthesis, DNA binding, and biological properties.

A new series of ellipticine derivatives, 1-(alkylamino)-5,11-dimethyl-9-methoxy-6H-pyrido[4,3-b]carbazoles, were synthesized as potential DNA intercalating antitumor drugs. The structure of these compounds were confirmed by 1H NMR spectroscopy and mass spectrometry. These compounds are able to bind to DNA with an affinity of about 10(6) M-1, and their intercalating characteristics (lengthening and unwinding of DNA) depend upon the length of the chain in position 1. The cytotoxicities of these compounds on L1210 and NIH-3T3 cells are quite similar, and fluorescence techniques showed that the compounds are localized mainly in the cytoplasmic granules of the cells. One of these compounds appears to show a very high antitumor activity (equivalent to the more active known ellipticine analogues: 10-[[gamma-(diethylamino)propyl]amino]-6-methyl-5H- pyrido[3',4':4,5]pyrollo[2,3-g]isoquinoleine (BD40), 1-[[gamma-(diethylamino)propyl]amino]-9-methoxyellipticine (BD84) and 2-[beta-(diethylamino)ethyl]-9-hydroxyellipticinium chloride (DEAE).

Alkaloids↗
PubMed1975

Ellipticine derivatives.

Several acyloxy and alkyl derivatives of ellipticine have been prepared. In addition, a modified synthesis leading to the hitherto unobtainable 8,9-dimethoxy- and 8,9-methylenedioxyellipticines is described. Some of the derivatives described herein exhibit antitumor activity. However, none of the compounds showed activity superior to that of the naturally occurring pyridocarbazoles, ellipticine and 9-methoxyellipticine.

Alkaloids↗
PubMed1985

Ellipticine derivatives with an affinity to the estrogen receptor, an approach to develop intercalating drugs with a specific effect on the hormone-dependent breast cancer.

In order to obtain breast tumor directed agents, we have prepared mixed compounds using estradiol or (E)-clomiphene as specific vectors of the breast tissue and a DNA intercalator from the ellipticine series as the cytotoxic agent. Among the newly synthesized ellipticine derivatives, only the 2-[3-aza-5-(3,17 beta-dihydroxy-1,3,5-estratrien-17 alpha-yl)-4-oxopentamethylene]ellipticinium bromide shows the desired properties, DNA intercalation and affinity for estrogen receptor. Competition experiments with estradiol on the hormone-dependent human MCF-7 breast cancer cell line demonstrate that a transport by the estrogen receptor system is not involved in the antitumor activity of derivative 24.

Alkaloids↗
PubMed1990

Sequence-selective binding of an ellipticine derivative to DNA.

The DNA sequence specificity of an ellipticine derivative bearing an aminoalkyl side chain has been determined by a variety of footprinting methods. The drug exhibits sequence selective binding and discriminates against runs of adenines or thymines. Binding is shown to occur at various sequences with a preference for GC rich regions of DNA. A large enhancement of DNAase I and of hydroxyl radical cleavage in regions rich in A's or T's is observed together with hyperreactivity of adenines towards diethylpyrocarbonate in the presence of drug. This indicates the occurrence of drug-induced changes in critical conformational features of DNA. The total absence of hyperreactivity of guanine residues towards diethylpyrocarbonate appears to be related to the sequence selectivity of drug binding. No alteration of the dimethyl sulphate and methylene blue-induced cleavage of DNA is observed. Irradiation of ellipticine derivative-DNA complexes with UV light followed by alkali treatment leads to selective photocleavage at guanine residues, consistent with the deduced degree of selectivity of the binding reaction.

Antineoplastic Agents↗
PubMed1983

Localization of ellipticine derivatives interacting with membranes. A fluorescence-quenching study.

The interaction with membranes of three anti-cancer drugs of the ellipticine family was studied by fluorescence quenching of membrane probes. The fluorescence of three probes, located at different levels in membranes, was quenched by addition of two types of ellipticine derivatives, one amphiphilic drug (9-methoxyellipticine) and two dipolar molecules (9-aminoellipticine and 9-hydroxyellipticine). By comparing the quenching curves obtained, the following can be proposed. a) 9-Methoxyellipticine can penetrate deeper in the lipid layers than 9-aminoellipticine and 9-hydroxyellipticine can. b) The three drugs are able to penetrate at least between the first methylene groups of the acyl chains of lipids in liposomes. c) In an isolated bacterial membrane, only 9-methoxyellipticine can be located in the region of the first methylene groups of lipids, the two dipolar drugs being adsorbed on the membrane surface. It was also shown that cholesterol hindered the penetration of 9-methoxyellipticine in the bilayer of liposomes.

Alkaloids↗
PubMed1990

Binding of ellipticine to beta-lactoglobulin. A physico-chemical study of the specific interaction of an antitumor drug with a transport protein.

The unprotonated form of the anti-tumor alkaloid ellipticine binds to beta-lactoglobulins A and B from bovine milk with an affinity constant of 7 +/- 3 x 10(5) M-1. There is one binding site/dimeric protein molecule (the stable form at medium pH). The attachment site is not the beta-barrel nor the hydrophobic site identified as the retinol site in beta-lactoglobulin but a domain located at the interface of the two monomeric units where the ligand lies close to Trp61 of both polypeptide chains. The positive binding enthalpy observed in temperature-jump relaxation experiments is overcome by a strong entropy increase, tentatively thought to result from water release at the binding domain. Accordingly, desolvation is assumed to be the rate-determining step in the process of ellipticine binding.

Animals↗
PubMedDate not supplied

Model systems for metabolism studies. Biomimetic oxidation of acetaminophen and ellipticine derivatives with water-soluble metalloporphyrins associated to potassium monopersulfate.

Some original water-soluble metalloporphyrins/KHSO5 systems were developed to mimic the metabolic biooxidation of drugs. Oxidation of acetaminophen and various ellipticine derivatives were used as model reactions. Oxidative products (mainly quinone-imine structures) were obtained in good yield after 2 min of reaction, for a catalyst/substrate ratio of 0.04. Iron(III) derivative of tetrasodium meso-tetrakis(p-sulfonatophenyl)porphyrin and manganese(III) derivative of tetraacetate meso-tetrakis(4-N-methyl-pyridiniumyl)-porphyrin were the best catalysts for the oxidation of acetaminophen and ellipticine compounds, respectively. At low catalyst concentration, initial turnover rates could rise up to 8 catalytic cycles/sec. In some conditions, these catalytic systems are nearly as efficient as horseradish peroxidase/H2O2. They might have a real future as oxidation catalysts, in complement to the use of purified monooxygenase and peroxidases, to predict the possible in vivo oxidative metabolite pathways.

Acetaminophen↗
PubMed1988

The biooxidation of cytotoxic ellipticine derivatives: a key to structure-activity relationship studies?

In the family of ellipticine derivatives, those with an amino-phenol or a masked amino-phenol structure are among the most cytotoxic compounds. Preliminary studies on 9-hydroxy- or 9-methoxyellipticines have shown that these molecules behave as "pro-alkylating" agents. In order to rationalize the "biooxidative alkylation" process for various ellipticine derivatives, we report in the present article (i) their electrochemical oxidation parameters, (ii) their biochemical oxidation, (iii) the ability of the oxidized forms to form adducts with nucleophiles, (iv) the biological activities, and (v) the electronic properties of oxidized forms. We present some possible correlations between the oxidizability, the electrophilicity of the oxidized derivatives, and the biological activities of the corresponding drugs.

Alkaloids↗
PubMed1995

Antiproliferative activity of some unsubstituted angular analogoues of ellipticine.

With the aim of obtaining further knowledge on the antiproliferative activity of pyrroloquinolines and isoquinolines, we prepared four unsubstituted angular pyridotetrahydrocarbazoles having a fourth non-aromatic ring, via modified Fischer synthesis. These compounds may be considered as simpler analogues of ellipticine. They induced evident antiproliferative effects in Ehrlich ascites and in CHO cells in vitro, but were ineffective on T2 bacteriophage. These compounds formed molecular complexes with DNA in vitro, while in CHO cells in vivo, they induced double-strand breaks in DNA and DNA-protein cross-links. These data suggest that these ellipticine analogoues are capable of inhibiting topoisomerase II, as the parent compound does. The most active derivative was 2N-5H-6,7,8,9-tetrahydropyrido[2,3-a]carbazole, which represents an interesting model for the study of new antitumor drugs.

Animals↗
PubMed1976

A possible mechanism of ellipticine-induced hemolysis.

Ellipticine (E) [5,11-dimethyl-6H-pyrido-(4,3-b)-carbazole, NSC-71795] is an antineoplastic agent which is active against L1210 lymphocytic leukemia in mice. Preclinical toxicologic studies demonstrated hemolysis in dogs and monkeys following intravenous administration of 1.5 mg/kg. This finding prompted this investigation of the mechanism of hemolysis and a study of the various factors that might ameliorate this effect. Initial experiments demonstrated that human red blood cells were completely hemolyzed at an E concentration of 10(-3) M, while a concentration of 10(-4) M stabilized red blood cells against 150 mOsM NaCl. The extent of hemolysis correlated well with the surface activities, lipophilic properties and cellular uptake of E and some of its derivatives (7,10-dimethylellipticine, isoellipticine, 9-methoxyellipticine and 11-demethylellipticine). The greatest hemolysis occurred with 7,10-dimethylellipticine and the least with 11-demethylellipticine. The cellular uptake of E and its derivatives was linear over a wide concentration range and was not temperature-dependent. Hemolysis could be blocked by citrate, sodium ethylenediamine tetraacetate, oxytetracycline and [(+/-)-1,2-bis(3,5-dioxopiperazin-1-y1)propane]. The inhibition of E uptake by citrate appears to be a noncompetitive process and has a K1 of 1.9 X 10(-3) M. These data suggest that Ca++ might be involved in the hemolytic process and in the cellular uptake of E. The intravenous administration of ellipticine to rhesus monkey caused severe hemolysis which could be prevented by simultaneous injection of citrate.

Alkaloids↗
PubMed1993

Synthesis and evaluation of 4-amino-substituted 7-methoxy (and 7-hydroxy)- 11-methyl (and 5,11-dimethyl)-10H-pyrido [2,3-b] carbazoles and 4-amino- substituted 11-methyl (and 5,11-dimethyl)-10H-pyrido[3',4':4,5] pyrrolo [3,2-g] quinolines, two new series related to antitumor ellipticine derivatives.

2-Acetyl-4-chloro-3-lithiopyridine ethylene glycol ketal (6b) was reacted with 3-formyl-5-methoxy-1-methyl-indole (9) and 3-formyl-1-methyl-1H-pyrrolo [3,2-c] pyridine (12), giving the corresponding expected alcohols. Reduction of these intermediates with triethylsilane trifluoroacetic acid and subsequent cyclodehydration then led to 4-chloro-7-methoxy-10,11-dimethyl-10H-pyrido [2,3-b] carbazole (8a) and the corresponding 7-aza-analog (8b). The synthesis of 4-chloro-11-methyl (and 5,11-dimethyl)-10-unsubstituted derivatives of these two series was performed through an independent pathway, involving condensation of conveniently substituted 2-amino carbazoles (17) and 7-amino-5H-pyrido [4,3-b] indoles (18) with 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, thermal cyclization of the resulting compounds with concomitant decarboxylation to the corresponding tetracyclic fused-4-quinolone systems and final chlorination with phosphorus oxychloride. Nucleophilic substitution of various 4-chloro derivatives was then easily performed in an excess of the required dialkylamino alkylamines at reflux and 4-amino substituted-7-hydroxy-10H- pyrido [2,3-b] carbazoles (25d-e) were obtained from 7-methoxy precursors (25a-b), by demethylation with boron tribromide in methylene chloride at -65 degrees C or with boiling 47% hydrobromic acid. Cytotoxicity determination of all new aminosubstituted derivatives and in vivo antitumor evaluation of the most active compounds clearly show that these two series of ellipticine analogs closely related to highly active products are devoid of antitumor properties in two experimental models shown to be sensitive to ellipticines. The place of the pyridinic nitrogen atom in these series has thus been demonstrated to play a crucial role in antitumor activity.

Animals↗
PubMed1997

Role of topoisomerase II beta in the resistance of 9-OH-ellipticine-resistant Chinese hamster fibroblasts to topoisomerase II inhibitors.

In the Chinese hamster lung cell line DC-3F/9-OH-E, made resistant to 9-OH-ellipticine and cross-resistant to other topoisomerase II inhibitors, the amount of topoisomerase II alpha is 4-5-fold lower than in the parental DC-3F cells. A mutation in position 1710 of topoisomerase II beta cDNA, generating a stop codon, completely abolishes the expression of this isoform in DC-3F/9-OH-E cells. To analyze the contribution of the loss of topoisomerase II beta to the resistance phenotype, DC-3F/9-OH-E cells were cotransfected with two plasmids, one conferring the resistance to G418, the other carrying the topoisomerase II beta cDNA. Among 200 G418-resistant clones, one was found to contain a topoisomerase II beta activity similar to that in the parental cells. These cells constitute an in vivo mammalian model to study the pharmacological role of topoisomerase II beta. In the transfected cells, different levels of cleavable complex formation and resistance reversion were observed with each topoisomerase II inhibitor examined. This work demonstrates that topoisomerase II beta is a pharmacological target for 9-OH-ellipticine, etoposide, or 4'-(9-acridinylamino)methanesulfon-m-anisidide and plays a role in the cytotoxicity of these agents. Furthermore, topoisomerase II beta is the preferential target for 4'-(9-acridinylamino)methanesulfon-m-anisidide. The loss of topoisomerase II beta activity in the DC-3F/9-OH-E cells is then in part responsible for their resistance to topoisomerase II inhibitors.

Amsacrine↗
PubMedDate not supplied

An ellipticine derivative (oxazolopyridocarbazolium) 3' linked to tetrathymidylate stacks intramolecularly with the nearest thymine at low concentration and head-to-tail intermolecularly at high concentration.

The solution conformation of a tetrathymidylate linked through an ester bond to an ellipticine derivative oxazolopyridocarbazolium (OPC) at the 3' position was investigated using one- and two-dimensional nmr experiments. Since the total electric charge of the OPC ring may influence self-association, we first determined the pKa of the oxazole cyclic acidic function. Nuclear Overhauser effect spectroscopy experiments showed that, at low concentration, the OPC stacks intramolecularly with the nearest thymine at the 3' end. At highest concentration, however, the OPC rings are self-associated. The stacking constant was calculated using 1H chemical shift dilution experiment. The conformational model suggested by P-nmr was tested by molecular mechanics computations.

Alkaloids↗
PubMed1994

The interaction of ellipticine derivatives with nucleic acids studied by optical and 1H-nmr spectroscopy: effect of size of the heterocyclic ring system.

The DNA interaction of derivatives of ellipticine with heterocyclic ring systems with three, four, or five rings and a dimethylaminoethyl side chain was studied. Optical spectroscopy of drug complexes with calf thymus DNA, poly[(dA-dT).(dA-dT)], or poly[(dG-dC).(dG-dC)] showed a 10 nm bathochromic shift of the light absorption bands of the pentacyclic and tetracyclic compounds upon binding to the nucleic acids, which indicates binding by intercalation. For the tricyclic compound a smaller shift of 1-3 nm was observed upon binding to the nucleic acids. Flow linear dichroism studies show that the geometry of all complexes is consistent with intercalation of the ring system, except for the DNA and poly[(dG-dC).(dG-dC)] complexes of the tricyclic compound, where the average angle between the drug molecular plane and the DNA helix axis was found to be 65 degrees. One-dimensional 1H-nmr spectroscopy was used to study complexes between d(CGCGATCGCG)2 and the tricyclic and pentacyclic compounds. The results on the pentacyclic compound show nonselective broadening due to intermediate chemical exchange of most oligonucleotide resonances upon drug binding. The imino proton resonances are in slow chemical exchange, and new resonances with upfield shifts approaching 1 ppm appear upon drug binding, which supports intercalative binding of the pentacyclic compound. The results on the tricyclic compound show more rapid binding kinetics and very selective broadening of resonances. The data suggest that the tricyclic compound is in an equilibrium between intercalation and minor groove binding, with a preference to bind close to the AT base pairs with the side chain residing in the minor groove.

Animals↗