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PubMed1998

Data of pre-clinical and early clinical trials of acriflavine and hydroxy-methyl-ellipticine reviewed, enriched by the experience of their use for 18 months to 6 years in combinations with other HIV1 virostatics.

Two virostatics which we discovered in 1990, acriflavine (ACF) and hydroxy-methyl-ellipticine (HEL) and shown active on HIV1 resistant to AZT have been introduced into combinations of four virostatics selected among ten available: themselves, plus zidovudine, zalcitabine, didanosine, lamivudine, stavudine, saquinavir, ritonavir, indinavir, the combinations were applied in 3-week sequences, differing from each other by drug rotation. Those which contained ACF may have more often a CD34 decrease than those containing neither ACF nor HEL, and they present more often a CD4 increase. No significant difference as far as side effects or beneficial effects could be detected after 18 months to 6 years, between sequences containing ACF or HEL or both, and sequences not containing any one of them.

Acriflavine↗
PubMed1980

Structure-activity relationships in a series of newly synthesized 1-amino-substituted ellipticine derivatives.

The synthesis of a series of 1-amino-substituted pyrido[4,3-b]carbazole derivatives, based on the substitution of corresponding 1-chloroellipticines, is reported. The cytotoxic properties on tumor cells grown in vitro, the in vivo acute toxicity of the most potent in vitro cytotoxic compounds, and the antitumor properties toward the L1210 leukemia system are described. No correlation between the apparent association constant to DNA and the in vitro cytotoxicity or the in vito antitumor efficiency could be observed in this series. 9-Hydroxylated derivatives were more cytotoxic in vitro than the corresponding 9-methoxylated compounds. However, their antitumor efficiencies on the in vivo experimental systems do not confirm the advantage of demethylation. The presence of a [(dialkylamino)alkyl]amino side chain at the 1 position of ellipticines increases the antitumor potency: 1-[[3-(diethylamino)propyl]amino]-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (5) is a very potent antitumor compound (% ILS of 134 on the L1210 leukemia system).

Alkaloids↗
PubMed1988

1-Amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles (gamma-carbolines) as tricyclic analogues of ellipticines: a new class of antineoplastic agents.

A series of 1-amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles that are structurally related to ellipticines by deletion of a ring have been synthesized in order to evaluate their DNA affinity, their in vitro cytotoxicity on L1210 cultured cells, and their in vivo antitumor activity. Among 24 derivatives that have been prepared and studied for the structure-activity relationship in this new class of antineoplastic agents, those that have a NH(CH2)3N(R)2 side chain (R = CH3 or C2H5) at their 1-position, a 4-methyl group, and an 8-OH substituent, either with a 5-NH or with a 5-NCH3 group, show the most potent cytotoxicities on L1210 cultured cells and in vivo antitumor properties in P388 and L1210 leukemia systems. In vivo antineoplastic activity of the most potent products was confirmed in P388 and L1210 leukemia systems. In vivo antineoplastic activity of the most potent products was confirmed on other mouse experimental tumors from the standard NCI screening:B16 melanoma and C38 adenocarcinoma.

Alkaloids↗
PubMed2000

Synthesis of 6H-indolo[2,3-b][1,6]naphthyridines and related compounds as the 5-Aza analogues of ellipticine alkaloids.

Treatment of 2-(1-alkynyl)phenyl isocyanates 6 with the iminophosphorane 14 produced in situ the benzoenynyl carbodiimides 15. Thermolysis of 15 under refluxing p-xylene furnished the 6H-indolo[2,3-b][1,6]naphthyridines 5, which could be regarded as the 5-aza analogues of ellipticine alkaloids. Similarly, condensation of 6 with the iminophosphorane 20 led to the formation of the 6H-indolo[2,3-b][1,5]naphthyridines 25 as the major isomer and the 10H- indolo[2,3-b][1,7]naphthyridines 26 as the minor isomer. The indolonaphthyridines 32, 33, and 34 having a methoxyl substituent were likewise synthesized. Treatment of the diisocyanate 43 with 2 equiv of the iminophosphorane 7 furnished 45 having two indoloquinoline units incorporated in a seven-fused-ring system.

Antineoplastic Agents↗
PubMed2002

Synthesis of novel heteroaromatics structurally related to ellipticine alkaloids via thermolysis of pyridannulated enyne-carbodiimides.

New synthetic pathways to the 5H-pyrido[3',4':4,5]pyrrolo[2,3-b]quinolines 6, the 6H-pyrido[3',4':4,5]pyrrolo[2,3-b][1,6]naphthyridines 7, and the 11H-pyrido[4',3':4,5]pyrrolo[2,3-b]quinolines 8 via thermolysis of the pyridannulated enyne-carbodiimides 14, 19, and 23 were established. These novel heteroaromatic systems are structurally related to ellipticine alkaloids and could serve as DNA-intercalating agents.

Alkaloids↗
PubMed2005

Regioselective intramolecular reactions of 2-indolylacyl radicals with pyridines: a direct synthetic entry to ellipticine quinones.

[reaction: see text] 2-Indolylacyl radicals generated from the corresponding selenoesters under hexabutylditin-hnu conditions undergo regioselective intramolecular reaction with unprotonated pyridines to give polycyclic indolylpyridyl ketones. For substrates bearing a (3-pyridyl)methyl moiety connected to the 3-position of the indole ring, the cyclization provides easy access to ellipticine quinones.

Cyclization↗
PubMed2005

Synthesis of ellipticine: a radical cascade protocol to aryl- and heteroaryl-annulated[b]carbazoles.

[reaction: see text] Imidoyl selanides, synthesized from amides, have been used as radical precursors of imidoyl radicals in cascade reactions. The novel radical cascade has been developed for the simple synthesis of the medicinally important aryl-annulated[b]carbazoles. The protocol has been exemplified with the high-yielding total synthesis of the anticancer alkaloid ellipticine.

Antineoplastic Agents↗
PubMed1995

A yeast type II topoisomerase selected for resistance to quinolones. Mutation of histidine 1012 to tyrosine confers resistance to nonintercalative drugs but hypersensitivity to ellipticine.

A mutant yeast type II topoisomerase was generated by in vitro mutagenesis followed by selection in vivo for resistance to the quinolone CP-115,953. The resulting mutant enzyme had a single point mutation which converted His1012 to Tyr (top2H1012Y). top2H1012Y was overexpressed in yeast, purified, and characterized in vitro. The mutant type II topoisomerase was slightly less active than the wild type enzyme, apparently due to a decreased affinity for DNA. The affinity of the mutant enzyme for ATP was similar to that of wild type topoisomerase II. As determined by DNA cleavage assays, top2H1012Y was resistant to CP-115,953 and etoposide both prior to and following the DNA strand-passage event. In marked contrast, the mutant enzyme displayed wild type sensitivity to amsacrine and was severalfold hypersensitive to ellipticine. A similar pattern of resistance was observed in yeast cells harboring the top2H1012Y allele. Thus, it appears that the mutant type II topoisomerase can distinguish between nonintercalative and intercalative agents. Finally, the His1012-->Tyr mutation defines a potential new drug resistance-conferring region on eukaryotic topoisomerase II.

Amino Acid Sequence↗
PubMed1985

Effects of ellipticine, flavone, and 7,8-benzoflavone upon 7,12-dimethylbenz[a]anthracene, 7,14-dimethyldibenzo[a,h]anthracene and dibenzo[a,h]anthracene initiated skin tumors in mice.

Varying doses of ellipticine (EL), flavone (FL), or 7,8-benzoflavone (78BF) were applied to mouse skin 5 min before an initiating dose of 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA), 47.5 nmol 7,14-dimethylbenzo[a,h]anthracene (DDBA), or 200 nmol dibenzo[a,h]anthracene (DBA) and the development of skin tumors in the mice then promoted by topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA). As expected, treatment with 78BF (37 nmol or 370 nmol) markedly inhibited the skin tumor initiation by DMBA (greater than 70%). High doses of FL (4500 nmol) or EL (410 nmol) also inhibited DMBA tumorigenesis (52% and 82%, respectively) but lower doses of FL (450 nmol) or EL (4.1 nmol) stimulated DMBA tumorigenesis (greater than 40%). As was the case with DMBA initiation, the higher doses of FL or EL inhibited DDBA skin tumorigenesis and the lower doses of these two modifiers stimulated the DDBA tumorigenesis. In contrast with the results with DMBA initiation, treatment with 78BF (370 nmol or 3700 nmol) slightly enhanced DDBA tumorigenesis (22% and 6%, respectively). Treatment with EL and FL at all doses tested stimulated DBA tumorigenesis (range 4-51%), while treatment with 370 nmol 78BF slightly stimulated DBA tumorigenesis (19%) and treatment with 3700 nmol slightly inhibited DBA tumorigensis (9%). The effects of a range of 78BF doses upon skin tumor initiation by 40 nmol DMBA were also investigated. While all doses of 78BF tested (0.37-370 nmol) inhibited the DMBA tumorigenesis, the dose response was not linear; treatment with 3.7 nmol 78BF resulted in more papillomas per mouse (12.20) than did treatment with either 0.37 nmol 78BF (8.70) or 37 nmol 78BF (5.97). It is concluded that modifiers such as 78BF, FL and EL may have a variable, dose-dependent effect upon skin tumor initiation by carcinogenic polycyclic arylhydrocarbons. Some implications of this proposal are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1976

Cardiovascular activity of 9-hydroxy-ellipticine.

The cardiovascular activity of 9-hydroxy-ellipticine (9-OH-E) has been studied on anaesthetized dogs. The drug has been administered intravenously in one dose ranging from 1 to 10 mg/kg. The variations in the myocardial contractility, the systemic haemodynamics, the respiration and the general metabolism of the anaesthetized dogs were studied to make evident the mechanism of 9-OH-E cardiostimulating action. 9-OH-E from 5 mg/kg i.v. stimulates the contractility of myocardium and improves the cardiac performances of the anaesthetized dogs. This heart-stimulating action is long-lasting and is not accompanied by any modification in the arterial blood pressure. It is inhibited or at least strongly attenuated by beta-adrenergic blocking agents and by the depletion of catecholamines.

Alkaloids↗
PubMed2004

Synthesis and cytotoxic activity of pyranocarbazole analogues of ellipticine and acronycine.

Various 2,2,5,11-tetramethyl- and 2,2,5,6,11-pentamethyl-2,6-dihydropyrano[3,2-b]carbazole derivatives were synthesized by condensation of 3-methylbut-2-enal or 3-chloro-3-methylbut-1-yne with an appropriate hydroxycarbazole. These compounds associate the tricyclic system responsible for the intercalating properties of ellipticine related drugs, with the dimethylpyran pharmacophore of acronycine derivatives. The study of the biological properties of the new pyrano[3,2-b]carbazole derivatives was carried out in vitro on L1210 murine leukaemia cell line. The three (+/-)-cis-diol diesters 15, 16, and 18 were the most active compounds.

Acronine↗
PubMed1991

Nephrotoxicity of an ellipticine derivative (N2-methyl-9-hydroxyellipticinium acetate) in rat: a defect of urinary concentrating ability.

The antitumor drug celiptium (N2-methyl-9-hydroxyellipticinium) is an ellipticine derivative effective in experimental tumors and in man. The major side effect is nephrotoxicity. The impairment of renal function is studied in rats following a single i.v. dose of 20 mg/kg celiptium and a long-term study (day 2 to day 60). A loss of body weight is noted in celiptium-treated animals between day 4 and day 15, and recovery occurs between day 15 and day 60. Histologic study shows cortical lesions characterized by focal necrosis of proximal tubules without any glomerular, interstitial, and vascular alterations on day 8. It is to be noted that any medullary lesions were not shown. A polyuria and a decreased creatinine clearance are reported on day 8. We were interested in a special study of this polyuria. For this study, rats were water deprived between day 6 and day 8 following celiptium administration. The decrease of urinary osmolality is not recovered after dehydration and exogenous vasopressin derivative (dD AVP) does not correct the renal concentration defect. AVP plasma levels increase after dehydration. These results suggest a pitressino-resistant urinary concentrating inability in celiptium-treated rats.

Acute Kidney Injury↗
PubMed1992

[Targeting of tumor cells by low density lipoproteins: principle and use of ellipticin derivatives].

Cells acquire cholesterol via de novo synthesis and high affinity receptor-mediated uptake of low-density lipoprotein (LDL). Some tumor tissues display increased receptor-mediated uptake of LDL as compared with the corresponding normal tissues. This increased LDL receptor activity is unexplained: a high cholesterol demand for cell growth or a mechanism directly linked to cell transformation. LDL has therefore been proposed as a potential carrier for chemotherapeutic agents. Various methods have been used to incorporate antineoplastic lipophilic drugs into LDL. The resultant drug-LDL complexes have been shown to be cytotoxic towards tumor cells in vitro, via the LDL receptor dependent pathway. However little is now on the in vivo fate of this complex. We described the incorporation of lipophilic derivatives of ellipticine into LDL by a fusion or facilitated transfer technique between drug containing microemulsions and LDL. The drug-LDL complex expressed similar metabolic activity, in vitro and in vivo, than native LDL. Initial experiments with melanoma B16 tumor-bearing mice suggest that LDL may be a potential drug carrier in the treatment of malignant diseases. The knowledge of the molecular mechanism of the expression of the LDL receptor in tumor cells and the ability to downregulate the LDL receptor in the normal tissues, will define the application field of this targeting approach.

Animals↗
PubMed1991

Comparison of anti-RNA properties of normal and ellipticine functionalized alpha and beta-oligonucleotides.

RNA is not cleaved as a consequence of the binding of RNase H to the duplex between RNA and a complementary alpha-oligodeoxyribonucleotide (oligo). In consequence targets have been selected which do not a priori require the action of RNase H to inhibit genetic expression. Two models have been used: The Friend Murine Leukemia Virus (F-MuLV) and the synthesis of rabbit beta globin.alpha-oligos trigger specific inhibitions in both systems. The functionalisation in 5' with the intercalating agent 9-NH2-ellipticine renders the oligos resistant to degradation and allows a direct action on cells.

Animals↗
PubMed1991

DNA-drug recognition and effects on topoisomerase II-mediated cytotoxicity. A three-mode binding model for ellipticine derivatives.

Cytotoxic effects and topoisomerase II-mediated DNA breaks induced in vitro by ellipticine derivatives were examined in connection with 1H NMR and circular dichroism (CD) studies on molecular structures and interactions of drugs with DNA. The compounds included four 9-hydroxyellipticine and two 7-hydroxyisoellipticine derivatives. Structure-activity relationships indicated that a change in nitrogen atom position in the pyridinic ring greatly affected drug effects both on topoisomerase II action and cytotoxicity to L1210 cells. The four 9-hydroxyellipticine derivatives yielded bell-shaped curves in in vitro topoisomerase II-mediated DNA break assays, whereas the two 7-hydroxyisoellipticine derivatives demonstrated an almost linear increase at the same concentration (0-10 microM). In both cases, the intensity of cleavage was modulated by the position and the degree of methylation on the pyridinic ring, and results were correlated with cytotoxic activity expressed as the in vitro ID50 values for L1210 leukemia cells. 1H NMR experiments performed on free drug molecules in solution revealed that the two protons (alpha and beta) contiguous to the biologically important hydroxy group were sensitive to changes in electron distribution produced by the distant chemical modifications and methylations of the pyridinic ring. A linear relationship was observed between the differences in chemical shifts of alpha and beta protons (delta delta alpha-beta) versus ID50 values. CD experiments indicated that, at weak ionic strength I = 0.02 and at pH 7, drugs interact with the poly[d(A-T)] duplex according to a "three-mode binding model" which is governed by the drug structure and the drug to DNA ratio. The intercalation mode was related to the induction of topoisomerase II-mediated DNA cleavage, while the external binding mode consecutive to intercalation was related to cleavage suppression. These two modes concerned the good intercalators 9-hydroxyellipticines. The third was found for the weak intercalators 7-hydroxyisoellipticines and was characterized by self-stacked molecules bound "outside" DNA, presumably in the minor groove. Ligands either could be intercalated partially or linked at the edge of bases with a small number of molecules filling intercalation sites, for the second alternative. In addition to having different binding modes, 9-hydroxyellipticines were better inducers of DNA distortions than 7-hydroxyisoellipticines. The incidence of the drug binding modes on DNA-topoisomerase II recognition was discussed in connection with the in vitro cytotoxic activity exhibited by the drugs.

Animals↗
PubMed1990

Comparative cytotoxicities of a series of ellipticine and olivacine derivatives on multidrug resistant cells of human and murine origins.

The MDR P-glycoprotein has been described as a major factor of multidrug resistance. This transmembrane glycoprotein acts like an energy dependent efflux pump which possesses a broad specificity. It seems to be acting as a pump requiring drug fixation prior to extrusion. With the aim of investigating which parameters influence the recognition of drugs by the MDR system, we have determined the toxicities of different drugs on human and murine sensitive and resistant cell lines. For this purpose we have isolated and characterized a human adriamycin-resistant cell line, CEM/Adr, which presents an MDR phenotype. The tested drugs were ellipticine and olivacine derivatives which differ through discrete lateral chain substitutions. The influence of lateral chain lipophilicity and nitrogen quaternarization on drug recognition was studied. Small modifications in the chemical structure of the drugs have induced large changes in their toxicities and in the cross-resistance levels of the MDR cells to the tested compounds. The cross-resistances of the murine and human cells to the various compounds were strikingly different. The validity of murine screening models in the selection of anti-tumor drugs for human therapy must therefore be questioned.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Caffeine modulates the effects of DNA-intercalating drugs in vitro: a flow cytometric and spectrophotometric analysis of caffeine interaction with novantrone, doxorubicin, ellipticine, and the doxorubicin analogue AD198.

Exposure of L1210 cells to DNA-intercalating antitumor drugs Novantrone (mitoxantrone; 20 ng/ml), doxorubicin (0.5 micrograms/ml), ellipticine (5 micrograms/ml), or the doxorubicin analogue AD198 (0.4 micrograms/ml), for 1 h, results in inhibition of cell proliferation, arrest of cells in the G2 phase of the cell cycle, and an increase in the number of cells entering higher DNA ploidy. These effects are significantly reduced when 5 mM concentrations of the methylxanthines caffeine or pentoxifylline are present either simultaneous with, or, in some cases, when added for 1 h immediately following pulse exposure to the drug. Both caffeine and pentoxifylline alone (5 mM) have little effect on cell growth or cell cycle progression. The possible mechanism of cell protection against intercalating drugs provided by caffeine was studied spectrophotometrically by measuring the interaction between Novantrone and the caffeine chromophore and in a model system using permeabilized L1210 cells and measuring the effect of caffeine in reducing binding of the intercalating dye acridine orange to cellular DNA and RNA. The data indicate that the observed protection of cells against intercalating drugs by caffeine or pentoxifylline is most likely a consequence of the direct interaction between the methylxanthines and the planar aromatic molecules of the intercalating drugs: formation of caffeine-drug complexes in solution effectively lowers the concentration of the free drug and thereby reduces its pharmacological activity. The principle of selective entrapment of the intercalator by compounds like caffeine may be considered in designing strategies to modulate the activity of intercalating drugs in vivo, e.g., in lowering drug toxicity when inadvertently applied at too high doses.

Acridine Orange↗