RESUMEN
Monocinnamoyl esters at position 2 of (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester group at position 1 and a cinnamoyl ester group at position 2 alkylated DNA slower than S23906-1. A strong correlation was observed between cytotoxicity and DNA alkylation kinetics, with slower alkylators displaying more potent antiproliferative activities. The most cytotoxic compounds proved to be significantly active in vivo against murine C-38 adenocarcinoma implanted in mice, but less potent than S23906-1.
Asunto(s)
Acronina/análogos & derivados , Acronina/toxicidad , Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/toxicidad , Acronina/síntesis química , Acronina/química , Acronina/farmacología , Animales , Antineoplásicos Alquilantes/química , Línea Celular Tumoral , ADN/química , Cinética , Ratones , Ratones Endogámicos C57BL , Trasplante HomólogoRESUMEN
The majority of DNA-binding small molecules known thus far stabilize duplex DNA against heat denaturation. A high, drug-induced increase in the melting temperature (Tm) of DNA is generally viewed as a good criterion to select DNA ligands and is a common feature of several anticancer drugs such as intercalators (e.g., anthracyclines) and alkylators (e.g., ecteinascidin 743). The reverse situation (destabilization of DNA to facilitate its denaturation) may be an attractive option for the identification of therapeutic agents acting on the DNA structure. We have identified the tumor-active benzoacronycine derivative S23906-1 [(+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2]acridin-7-one] as a potent DNA alkylating agent endowed with a helicase-like activity. Using complementary molecular approaches, we show that covalent binding to DNA of the diacetate compound S23906-1 and its monoacetate analogue S28687-1 induces a marked destabilization of the double helix with the formation of alkylated ssDNA. The DNA-bonding properties and effects on DNA structure of a series of benzoacronycine derivatives, including the dicarbamate analogue S29385-1, were studied using complementary biochemical (electromobility shift assay, nuclease S1 mapping) and spectroscopic (fluorescence and Tm measurements) approaches. Alkylation of guanines in DNA by S28687-1 leads to a local denaturation of DNA, which becomes susceptible to cleavage by nuclease S1 and significantly decreases the Tm of DNA. The drug also directly alkylates single-strand DNA, but mass spectrometry experiments indicate that guanines in duplexes are largely preferred over single-stranded structures. This molecular study expands the repertoire of DNA-binding mechanisms and provides a new dimension for DNA recognition by small molecules.
Asunto(s)
Acronina/análogos & derivados , Acronina/toxicidad , Antineoplásicos/toxicidad , ADN de Cadena Simple/efectos de los fármacos , ADN/química , ADN/efectos de los fármacos , Conformación de Ácido Nucleico/efectos de los fármacos , Alquilantes/toxicidad , Antraciclinas/toxicidad , ADN de Cadena Simple/química , Sustancias Intercalantes/toxicidad , Cinética , Desnaturalización de Ácido Nucleico , Oligodesoxirribonucleótidos/químicaRESUMEN
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.
Asunto(s)
Acronina/análogos & derivados , Acronina/síntesis química , Acronina/toxicidad , Antineoplásicos/toxicidad , Carbazoles/toxicidad , Elipticinas/toxicidad , Piranos/toxicidad , Animales , Antineoplásicos/síntesis química , Carbazoles/síntesis química , Línea Celular Tumoral , Elipticinas/síntesis química , Leucemia L1210/tratamiento farmacológico , Leucemia L1210/patología , Ratones , Piranos/síntesis químicaRESUMEN
A series of novel azapyranoxanthenones, bearing structural similarity to the acridone alkaloid acronycine have been designed and synthesized. Their in vitro cytotoxicities against the murine L1210 leukemia and the human solid tumor HT-29 cell lines have been investigated. The new derivatives exhibited interesting cytotoxic activity and were more potent than the parent compound.
Asunto(s)
Acronina/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Acridinas/química , Acridonas , Acronina/química , Acronina/toxicidad , Animales , Antineoplásicos/química , Proteínas de Ciclo Celular/análisis , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Concentración 50 Inhibidora , Leucemia L1210/tratamiento farmacológico , RatonesRESUMEN
The novel 6-dialkylaminoalkylamino-3,3,12-trimethyl-3,12-dihydro-7H-pyrano[2,3-c]acridine-7-ones 5-11 and their benzo [b]pyrano[2,3-h]acridine-7-one counterparts 12-18 were prepared by treatment of acronycine (1) or benzo[b]acronycine (4) with an excess of the appropriate dialkylaminoalkylamine. In both series, the introduction of a dialkylaminoalkylamino side chain at position 6 resulted in a significant increase of the cytotoxic activity against L1210 cells when compared with the parent compounds bearing a methoxy group, accompanied with an increased potency to arrest cells in the G2 + M phases of the cell cycle.