RESUMEN
Podophyllotoxin, a natural lignan, is a good inhibitor of tubulin polymerization with antitumoral properties but it is too toxic for therapeutic use. In order to obtain less toxic drugs, several heterolignans have been prepared. We presented the synthesis and preliminary pharmacological properties of 4-aza-2,3-didehydropodophyllotoxins (dihydropyrrole [3,4-b]quinolin-1-ones), a new azalignan series. A straightforward synthesis was described according to a multicomponent reaction in a one-pot procedure. Starting from an aniline, an aromatic aldehyde, and a cyclic B-diketone, many substituted analogues could be prepared. Our lead, the 4-aza-2,3-didehydropodophyllotoxin, is extremely cytotoxic on various tumor cell lines, active in vivo on murine tumors. Like podophyllotoxin, this drug inhibits microtubule assembly without any effect on depolymerization.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Aza/síntesis química , Podofilotoxina/análogos & derivados , Podofilotoxina/síntesis química , Animales , Antineoplásicos/farmacología , Compuestos Aza/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Microtúbulos/efectos de los fármacos , Podofilotoxina/farmacología , Relación Estructura-ActividadRESUMEN
We report the synthesis, DNA-binding and cleaving properties, and cytotoxic activities of R-128, a hybrid molecule in which a bis-pyrrolecarboxamide-amidine element related to the antibiotic netropsin is covalently tethered to a phenazine-di-N-oxide chromophore. The affinity and mode of interaction of the conjugate with DNA were investigated by a combination of absorption spectroscopy, circular dichroism, and electric linear dichroism. This hybrid molecule binds to AT-rich sequences of DNA via a bimodal process involving minor groove binding of the netropsin moiety and intercalation of the phenazine moiety. The bidentate mode of binding was evidenced by linear dichroism using calf thymus DNA and poly(dA-dT).(dA-dT). In contrast, the drug fails to bind to poly(dG-dC).poly(dG-dC), because of the obstructive effect of the guanine 2-amino group exposed in the minor groove of this polynucleotide. DNase I footprinting studies indicated that the conjugate interacts preferentially with AT-rich sequences, but the cleavage of DNA in the presence of a reducing agent can occur at different sequences not restricted to the AT sites. The main cleavage sites were detected with a periodicity of about 10 base pairs corresponding to approximately one turn of the double helix. This suggests that the cleavage may be dictated by the structure of the double helix rather than the primary nucleotide sequence. The conjugate which is moderately toxic to cancer cells complements the tool box of reagents which can be utilized to produce DNA strand scission. The DNA cleaving properties of R-128 entreat further exploration into the use of phenazine-di-N-oxides as tools for investigating DNA structure.
Asunto(s)
ADN/metabolismo , Netropsina/química , Fenazinas/química , Animales , Antivirales/química , Antivirales/metabolismo , Sitios de Unión , Bovinos , Supervivencia Celular/efectos de los fármacos , Dicroismo Circular , ADN/química , Huella de ADN , ADN Bacteriano/química , ADN Bacteriano/metabolismo , Células HL-60 , Humanos , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Netropsina/metabolismo , Plásmidos/química , Plásmidos/metabolismo , Polidesoxirribonucleótidos/química , Polidesoxirribonucleótidos/metabolismo , Temperatura , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Antineoplásicos/síntesis química , Flavinas/síntesis química , Oligopéptidos/síntesis química , Fármacos Fotosensibilizantes/síntesis química , Pirroles/síntesis química , Aminoimidazol Carboxamida/metabolismo , Aminoimidazol Carboxamida/farmacología , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Dicroismo Circular , ADN/metabolismo , Flavinas/metabolismo , Flavinas/farmacología , Células HeLa/efectos de los fármacos , Células HeLa/efectos de la radiación , Humanos , Luz , Oligopéptidos/farmacología , Fármacos Fotosensibilizantes/metabolismo , Fármacos Fotosensibilizantes/farmacología , Pirroles/metabolismo , Pirroles/farmacologíaRESUMEN
Three 9,10-anthraquinone-oligopyrrolecarboxamide hybrids have been prepared as potential DNA minor groove cleaving agents. Each conjugate was designed to contain a bis- or tris-pyrrolecarboxamide moiety related to netropsin or distamycin covalently linked to a 2-substituted anthraquinone chromophore capable of triggering photocleavage of DNA. AQ(NC)-Dist, having three pyrrole rings, is related to distamycin. AQ(NC)-Net and AQ(CN)-Net are related to netropsin; they differ only by the orientation of the amide bond between the anthraquinone and the netropsin moiety. The binding properties of these compounds to various natural DNAs have been studied by footprinting and circular dichroism. The introduction of the chromophore does not abolish the capacity of the drugs to recognize AT-rich sequences in DNA selectively. There is apparently little correlation between this property and the ability to trigger photo-induced DNA cleavage. AQ(CN)-Net is almost totally inactive in the cleavage assays whereas it manifestly binds selectively to AT-rich tracts. With AQ(NC)-Net and AQ(NC)-Dist, complete conversion of form I to form II of circular DNA is obtained. Moreover, in most cases the cleavage of DNA proved to be non-specific.
Asunto(s)
Amidas/química , Antraquinonas/química , ADN/efectos de los fármacos , Amidas/síntesis química , Amidas/farmacología , Antraquinonas/síntesis química , Antraquinonas/farmacología , Secuencia de Bases , Huella de ADN , Desoxirribonucleasa I/metabolismo , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
We have studied the binding of the hybrid netropsin-flavin (Net-Fla) molecule onto four sequences containing four A. T base pairs. Molecular mechanics minimizations in vacuo show numerous minimal conformations separated by one base pair. 400 ps molecular dynamics simulations in vacuo have been performed using the lowest minima as the starting conformations. During these simulations, the flavin moiety of the drug makes two hydrogen bonds with an amino group of a neighboring guanine. A 200 ps molecular dynamics simulation in explicit water solution suggests that the binding of Net-Fla upon the DNA substrate is enhanced by water bridges. A water molecule bridging the amidinium of Net-Fla to the N3 atom of an adenine seems to be stuck in the drug-DNA complex during the whole simulation. The fluctuations of the DNA helical parameters and of the torsion angles of the sugar-phosphate backbone are very similar in the simulations in vacuo and in water. The time auto-correlation functions for the DNA helical parameters decrease rapidly in the picosecond range in vacuo. The same functions computed from the water solution molecular dynamics simulations seem to have two modes: the rapid mode is similar to the behavior in vacuo, and is followed by a slower mode in the 10 ps range.
Asunto(s)
ADN/química , ADN/metabolismo , Flavinas/química , Netropsina/química , Netropsina/metabolismo , Sitios de Unión , Simulación por Computador , Transferencia de Energía , Flavinas/metabolismo , Modelos Moleculares , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Soluciones , Factores de Tiempo , Vacio , AguaRESUMEN
In an attempt to obtain sequence specific DNA-cleaving molecules, we have synthesized a series of hybrid minor groove binders composed of a photoactiveable isoalloxazine (flavin) chromophore linked through a polymethylenic chain to a bis-pyrrolecarboxamide moiety related to netropsin. Like netropsin, the hybrid derivatives preferentially bind to A+T-rich sequences. Activation of the flavin chromophore by visible light results in the appearance of single strand breaks in the vicinity of the DNA binding site. We have further investigated the cleavage affinity properties of one of these compounds referred to as netropsin-flavin (Net-Fla) and considered as representative of the series. Net-Fla cleaves only one strand at a specific locus downstream of 5'-AAAT-3', upstream of 5'-TAAA-3' and on either side of a 5'-AAAA-3' sequence. Net-Fla cleaves both strands downstream to 5'-AATT-3'. This makes the properties of Net-Fla similar to that of a restriction endonuclease and provides additional insight into establishing the rules for the readout of B-DNA helix by non-nucleotidic compounds. Using molecular modeling, we show that Net-Fla binds to an asymmetric site in one orientation. The values of the energetic minima lie in the same order as expected from the cleavage patterns, which suggests that the oriented cleavage is a consequence of a sequence-oriented binding of Net-Fla in the DNA minor groove.
Asunto(s)
ADN de Cadena Simple/metabolismo , Flavinas/metabolismo , Netropsina/metabolismo , Secuencia de Bases , Daño del ADN , Huella de ADN , Flavinas/genética , Hidrólisis , Conformación Molecular , Datos de Secuencia MolecularRESUMEN
Six heterocyclic quinones with topoisomerase I inhibiting properties and cytotoxic activities on L1210 leukemia cells were studied for their mutagenicity in four strains of Salmonella typhimurium. The tested compounds are 3-methoxyindolo[3,2-c]quinoline-1,4-diones and their derivatives in which the common pyrroloquinoline nucleus is annelated either with a benzene or a cyclohexane on a pyridine ring. Almost all quinones were found to be direct-acting mutagens at different levels in all strains, mainly TA97a and TA98. Relations were established between their structure and their mutagenic activities. The mutagenicity was found to be influenced (i) by the nature of the fourth nucleus: the pyridinic compounds were the most active, the non-aromatic ones were practically inactive; (ii) by the presence of a methyl group in the 6-position that decreased the mutagenicity. Then, the mutagenic properties were compared with the topoisomerase I inhibiting property that is one of the possible mechanisms of action for these cytotoxic quinones. The results indicated a correlation between mutagenicity and enzyme inhibiting properties.
Asunto(s)
Leucemia L1210/patología , Mutágenos/toxicidad , Quinonas/farmacología , Inhibidores de Topoisomerasa I , Animales , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Pruebas de Mutagenicidad , Quinonas/toxicidad , Salmonella typhimurium/genética , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
We show that oligodeoxyribonucleotides (oligos) composed of alpha- and beta-anomeric sections can be used as antisense compounds. An octamer has been chosen as an effector domain to form a substrate for RNaseH. This octamer is complementary to the translation start site of the pim-1 protooncogene mRNA. Chimeric alpha-beta oligos and their beta-analogs have a similar binding affinity for their target. These oligos also direct efficient RNaseH-mediated cleavage of target mRNA. Among all alpha-beta oligos studied, one with an alpha-fragment bound by its 3'-end to the 3'-end of the beta-octamer is the most resistant to nucleolytic digestion in biological media. The alpha-beta oligos have been found to inhibit in vitro translation of pim-1 RNA with specificity.
Asunto(s)
Oligonucleótidos Antisentido/farmacología , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/genética , Animales , Secuencia de Bases , Sangre , Medios de Cultivo , Eritroblastos , Globinas/genética , Humanos , Hidrólisis , Ratones , Datos de Secuencia Molecular , Oligonucleótidos Antisentido/metabolismo , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-pim-1 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Conejos , Ribonucleasa H/metabolismoRESUMEN
New 1H-pyrrolo [3,2-c] quinoline-6,9-diones, 11H-indolo [3,2-c] quinoline-1,4-diones and 7,8,9,10-tetrahydro-11H-indolo [3,2-c] quinoline-1,4-diones, either unsubstituted or methylated, have been synthesized and evaluated for antitumor activity. They were compared to previously described quinones which bear either a methoxy group or an aziridinyl substituent on the quinone nucleus in order to establish structure-activity relationships and to obtain compounds as active as aziridinylquinones, but with less toxicity. A new synthetic route was developed using dimethoxy derivatives as key compounds that reacted with ceric ammonium nitrate (CAN) to give quinones by oxidation demethylation. The biological results obtained in vitro indicated that: (i) new quinones display cytotoxicity higher than that of the methoxyquinones; (ii) unsubstituted compounds are the most active; (iii) methylation of the pyrrole NH has no influence on unsubstituted quinones, but affords inactive derivatives when the quinone nucleus is methylated; (iv) compared to the aziridinyl-quinones, some compounds are equally active or more active. Despite the cytotoxicity exerted in vitro, we could not find evidence for any antitumor activity of quinones against in vivo P388 murine leukemia.
Asunto(s)
Antineoplásicos/síntesis química , Quinolinas/síntesis química , Animales , Antineoplásicos/farmacología , Femenino , Leucemia P388/tratamiento farmacológico , Ratones , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
In an attempt to obtain DNA sequence-specific cleaving molecules, we have synthesized two types of hybrid groove binders composed of an isoalloxazine (flavin) chromophore linked through a polymethylenic chain to either a bis- or a tris(pyrrolecarboxamide) moiety related to netropsin and distamycin, respectively. In both types of molecules, the polymethylenic chain is linked to the alloxazine ring either in the N10 position or in the N3 position. As netropsin and distamycin, the hybrid derivatives preferentially bind to A + T-rich sequences and recognize sequences such as 5'-ATTT. Upon visible light irradiation the flavin moiety undergoes a redox cycling process generating superoxide anion and hydroxyl radical. Generation of oxy radicals appears to be more efficient with the hybrids in which the polymethylenic chain is linked at the N10 position. The generation of oxy radicals results in the occurrence of single strand break in supercoiled DNA. Breaks preferentially occur in the vicinity of A + T-rich sequences. The advantage of flavin relative to other oxy radicals generating compounds such as ferrous-EDTA is that it does not require chemical reduction but can be reduced either by visible light or by cellular enzymes, both conditions being compatible with pharmacological constraints.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , ADN/metabolismo , Flavinas/síntesis química , Flavinas/farmacología , Netropsina/síntesis química , Netropsina/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Dicroismo Circular , Reactivos de Enlaces Cruzados/síntesis química , Reactivos de Enlaces Cruzados/química , ADN/efectos de los fármacos , Daño del ADN , Dermatoglifia del ADN , ADN Circular/efectos de los fármacos , ADN Circular/metabolismo , ADN Superhelicoidal/efectos de los fármacos , ADN Superhelicoidal/metabolismo , Distamicinas/síntesis química , Distamicinas/metabolismo , Distamicinas/farmacología , Flavinas/metabolismo , Netropsina/metabolismo , Fotoquímica , Pirroles/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ViscosidadRESUMEN
A new type of chimeric oligonucleotides composed of alpha- and beta-sections is described. The sequence of eight beta-nucleotides flanked at 3'- or/and 5'-ends by nuclease-resistant alpha-oligonucleotides has been chosen as an effector domain to form a substrate for RNase H. The synthesized oligonucleotides are complementary to the translation initiation site of the pim protooncogene mRNA. We used the chemical ligation method to prepare the chimeric oligonucleotides. The thermal stability of heteroduplexes formed by the alpha beta oligonucleotides with a complementary strand is not significantly altered compared to that of their beta-analogs. These oligonucleotides promote efficient RNase H-mediated cleavage of pim mRNA. Among the alpha beta oligonucleotides studied, one with an alpha-fragment bound by its 3'-end to the 3'-end of the beta-octanucleotide proved to be the most resistant to nucleolytic digestion in human plasma, calf serum, and murine fibroblast lysate. This alpha beta oligonucleotide directs more specific RNA cleavage by RNase H than its beta beta counterpart.
Asunto(s)
Oligonucleótidos Antisentido/síntesis química , ARN Mensajero/química , Secuencia de Bases , Medios de Cultivo , Modelos Biológicos , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Oligonucleótidos Antisentido/química , Proto-Oncogenes , Ribonucleasa H , TemperaturaRESUMEN
A series of seven 6-methylindolo[3,2-c]quinoline-1,4-diones substituted either in the 2 position or in 3 position by various groups were examined for their ability to induce mutation in the Ames test at several concentrations in four strains of Salmonella typhimurium (TA97, TA98, TA100, and TA102). First, relationships were established between their mutagenic activities and either the nature or the position of the substituent on the quinonic nucleus. Compounds substituted in the 2 position were less mutagenic than the 3 isomers. In the second study, the mutagenic properties were compared to the in vitro antitumor activity. Interestingly, some very cytotoxic quinones were only weak mutagens. So where the cytotoxicity is similar, the less mutagenic compounds may be suitable for clinical use as antitumor drugs, in order to avoid important side effects; the Ames test can then be used guide the selection of molecules for further in vivo antitumor screening. It can also be very helpful in selecting the best candidate molecules to be synthesized.
Asunto(s)
Mutágenos/toxicidad , Quinolonas/toxicidad , Animales , Biotransformación , Supervivencia Celular , Leucemia L1210 , Mutágenos/química , Mutágenos/farmacocinética , Quinolonas/química , Quinolonas/farmacocinética , Salmonella typhimurium/efectos de los fármacos , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
With the aim of obtaining new inhibitors of topoisomerases, we have evaluated various heterocyclic quinone derivatives for their ability to induce topoisomerase I (Topo I)- or Topo II-associated DNA breaks, using P388 cell nuclear extract. Several compounds belonging to the indolo[3,2-c]quinoline-1,4-dione series have been shown to possess DNA-cleavage activity. Further analysis using purified Topo I and II preparations has indicated that the members of the series stimulate cleavable complex formation of both Topo I and II. 3-Methoxy-11H-pyrido[3',4':4,5]pyrrolo[3,2-c] quinoline-1,4-dione (AzalQD), one of the most active members of the series, stimulates cleavable complex formation and inhibits the catalytic activities of both eukaryotic Topo I and II, with, however, less potency than camptothecin and etoposide. Topo I cleavage site patterns for AzalQD and camptothecin were found to be nearly identical, with, however, some differences in cleavage site intensities. Use of filter binding assays also indicates that AzalQD is at least 10 times more potent against Topo I than against Topo II. Structure-activity relationships of indoloquinolinedione derivatives have been established and have shown that Topo I and II inhibitions are strongly linked, with a dose-selective preference towards Topo I. AzalQD does not display detectable DNA-unwinding properties. AzalQD induces a preferential cytotoxicity for the yeast strain JN2-134 bearing the human top1 gene under the control fo the GAL1 promoter, indicating that Topo I inhibition is responsible for the yeast cytotoxicity. These data indicate that AzalQD and its structural analogs represent a new distinct class of eukaryotic Topo I and II inhibitors.
Asunto(s)
Quinonas/farmacología , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa II , Camptotecina/farmacología , ADN/efectos de los fármacos , ADN/metabolismo , Daño del ADN , Dactinomicina/farmacología , Humanos , Relación Estructura-Actividad , Levaduras/efectos de los fármacos , Levaduras/enzimologíaRESUMEN
Four antitumoral 5,8-quinazolinediones were examined for their ability to induce mutation in Salmonella typhimurium. Each compound was tested at several concentrations in 4 strains. Relationships were established between the structure of the quinones and their mutagenic activities. The mutagenicity was influenced by (i) the nature of the substituent(s) of the quinonic moiety: the methoxyquinone had no mutagenic properties and the aziridinylquinones were mutagenic in the 4 strains with or without activation by S9 mix; (ii) the presence or the absence of a diaminopolymethylenic chain in the 4 position; (iii) the monomeric or the dimeric structure of the tested compound. Interestingly, the data indicated that the aziridinylquinazolinedione bearing the dimethylaminopropylamino chain in the 4 position was less mutagenic and had greater antitumor activity than the dimeric quinone.
Asunto(s)
Antineoplásicos/efectos adversos , Aziridinas/toxicidad , Quinazolinas/toxicidad , Aziridinas/química , Extractos Hepáticos , Pruebas de Mutagenicidad , Quinazolinas/química , Salmonella typhimurium/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.
Asunto(s)
Antineoplásicos/síntesis química , Aziridinas/síntesis química , Neoplasias Experimentales/tratamiento farmacológico , Quinazolinas/síntesis química , Animales , Aziridinas/química , Aziridinas/farmacología , Aziridinas/uso terapéutico , Neoplasias de la Mama , División Celular/efectos de los fármacos , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Leucemia L1210 , Leucemia Experimental/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Estructura Molecular , Quinazolinas/química , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Sarcoma Experimental/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
With the aim of obtaining new antitumor drugs more active than previously described 11H-indolo[3,2-c]quinoline-1,4-diones and 7,8,9,10-tetrahydro-11H-indolo[3,2-c]quinoline-1,4-diones, the synthesis and activities of a series of 3-substituted 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones and of 7,8,9,10-tetrahydro-11H-pyrido-[3',4':4,5]pyrrolo[3,2-c] quinoline-1,4-diones were studied. Some quinones were more cytotoxic in vitro towards L1210 leukemia cells but were not active in vivo towards murine P388 leukemia.
Asunto(s)
Antineoplásicos/síntesis química , Indoles/síntesis química , Piridinas/síntesis química , Pirroles/síntesis química , Quinolonas/síntesis química , Animales , Fenómenos Químicos , Química , Indoles/farmacología , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Ratones , Piridinas/farmacología , Pirroles/farmacología , Quinolonas/farmacologíaRESUMEN
The synthesis of 2,3-bis(2-pyridyl)-5,8-quinoxalinediones has been carried out in order to provide new antitumor drugs related to streptonigrin. Some derivatives have been found to possess significant cytotoxic properties and their mechanism of action has been studied. They were found to induce single-strand cleavage of covalently closed circular DNA (ccc-DNA). This biological activity requires an apparent in situ reduction (NADH activation) of the quinone to a hydroquinone or semiquinone radical, is facilitated by the presence of Cu(II), and involves activation of molecular oxygen to highly reactive radical species. Thus, although less active than the parent drugs, these molecules provide an attractive rationale for the observed cytotoxic and antitumor potency, as well as the cell-free single strand DNA cleavage efficacy of that family of drugs.
Asunto(s)
Quelantes/síntesis química , Piridinas/síntesis química , Quinoxalinas/síntesis química , Animales , Supervivencia Celular/efectos de los fármacos , Fenómenos Químicos , Química , Cobre , ADN/efectos de los fármacos , Daño del ADN , Fluorescencia , Radicales Libres , Leucemia L1210/patología , Desnaturalización de Ácido Nucleico , Piridinas/farmacología , Quinoxalinas/farmacología , ViscosidadRESUMEN
4-Chloro-8-methoxy-11H-indolo[3,2-c]quinoline could be obtained from 8-chloro-2,3-dihydro-1H-quinolin-4-one and 4-methoxyphenylhydrazine by applying Fischer's indole synthesis. Its nitration led to the 7-nitro derivative which was reduced to 7-amino-4-chloro-8-methoxy-11H-indolo[3,2-c]quinoline when Raney nickel was employed as a catalyst and to 7-amino-8-methoxy-11H-indolo[3,2-c]quinoline when palladium charcoal was used. Oxidation of the amines by potassium nitrosodisulfonate produced the corresponding 11H-indolo[3,2-c]quinoline-7,10-diones. Displacement of the methoxy group by (N,N-diethylamino)ethylamine or by N-methylpiperazine afforded the 8-aminoquinones. The quinones unsubstituted at the 4-position were more cytotoxic than the previously described 2-methoxy-11H-indolo[3,2-c]quinoline-1,4-diones.