RESUMEN
The synthesis of dihydroxybenzoperimidine derivatives, which are chromophore-modified dihydroxyanthracenediones with an additional pyrimidine ring incorporated into the chromophore, is reported. These derivatives are structurally related to the antitumor agent mitoxantrone. Their synthesis was carried out by the reaction of 6-amino-8,11-dihydroxy-7H-benzo[e]perimidin-7-one (5) or 6,8, 11-trihydroxy-7H-benzo[e]perimidin-7-one (10) with a number of respective (alkylamino)alkylamines. The dihydroxybenzoperimidine derivatives exhibited in vitro cytotoxic activity against murine leukemia L1210 and human leukemia HL60 cell lines comparable to that of mitoxantrone. These compounds also exhibited a range of in vitro activity against the human MDR-type resistant leukemia K562R cell line with the MDR phenotype. The most active compound of this series, namely 6a, exhibited potent in vitro cytotoxic activity against a panel of human cell lines. Furthermore, in contrast to both mitoxantrone and doxorubicin, it displayed little cross-resistance in cell lines characterized by a MDR phenotype. Cell cycle analysis in the sensitive HT-29 and mitoxantrone-resistant HT-29/Mx (not identified resistance mechanism) cell lines has revealed that both mitoxantrone and 6a induce a G2/M block. However, while the proportion of apoptotic cells after mitoxantrone treatment is similar for both sensitive and resistant cell lines, it is much lower for 6a. Compound 6a tested against P388 murine leukemia in vivo displayed a significant antitumor effect (%T/C 196 at an optimal dose of 10 mg/kg). The property of overcoming the cross-resistance was maintained also in in vivo efficacy studies, where no difference was observed in the antitumor activity of compound 6a against the A2780 human tumor xenograft and its MDR A2780/Dx subline. We conclude that benzoperimidines, if properly substituted, constitute a novel class of compounds that can overcome multidrug resistance.
Asunto(s)
Antineoplásicos/síntesis química , Quinazolinas/síntesis química , Animales , Antracenos/síntesis química , Antracenos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Humanos , Leucemia P388/tratamiento farmacológico , Ratones , Mitoxantrona/química , Mitoxantrona/farmacología , Quinazolinas/farmacología , Células Tumorales CultivadasRESUMEN
A series of 3-(aminoalkyl)-2,7-dihydro-6-nitropyrimido [4,5,6-kl] acridin-2-ones 3, strictly related to the pyrazoloacridines 1, have been synthesized. Thus, the reaction of the suitable 1-(aminoalkyl)amino-9, 10-dihydro-9-imino-4-nitroacridine 2 with ethyl chloroformate afforded the pyrimidoacridines 3a-f. By hydrolysis in hydrobromic acid of the 10-methoxy derivatives 3d-f, the 10-hydroxy derivatives 3g-i were obtained. The pyrimidoacridines 3a-i were tested in vitro for their cytotoxic activity against L1210 murine leukemia and HT29 human colon adenocarcinoma cell lines, showing significant potency of growth inhibition. Different DNA-binding assays as well as attempts to correlate cytotoxicity and DNA affinity have been carried out.
Asunto(s)
Acridinas/síntesis química , Acridinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Acridinas/metabolismo , Adenocarcinoma/patología , Animales , Antineoplásicos/metabolismo , ADN/metabolismo , Humanos , Leucemia L1210/patología , Espectroscopía de Resonancia Magnética , Ratones , Células Tumorales CultivadasRESUMEN
A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.
Asunto(s)
Acridinas/farmacología , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos , Acridinas/síntesis química , Animales , Antineoplásicos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucemia L1210/tratamiento farmacológico , Células Tumorales CultivadasRESUMEN
In the constant search for new compounds endowed with antitumor activity we have synthesized a series of anthraquinone hydrazones, which can bee seen either as opened-cycle modified anthrapyrazoles or as chromophore-modified anthracenediones. Seven 9,10-anthraquinone monoalkylaminoalkylhydrazones (3c-i) were synthesized from 10,10-dibromoanthrone (4) and a suitable N-alkylhydrazine. The hydrazones were converted into hydrochlorides and tested for their cytotoxic activity against L1210 murine leukemia cells. Two of them possess marginal activity in vitro.
Asunto(s)
Antraquinonas/síntesis química , Antineoplásicos/síntesis química , Hidrazonas/síntesis química , Animales , Antraquinonas/química , Antraquinonas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Leucemia L1210/tratamiento farmacológico , RatonesRESUMEN
A class of chromophore-modified anthracenediones with an additional pyrimidine ring incorporated into the chromophore system has been obtained in an attempt to provide compounds with diminished peroxidation activity and thus potentially lowered cardiotoxicity. Their synthesis was carried out by the reaction of 6-amino- or 6-hydroxy-7H-benzo[e]perimidin-7-one with a number of alkylamines. Potent activity was demonstrated in vitro against murine L1210 leukemia cells (equipotent with ametantrone) as well as against P388 leukemia in vivo (% T/C = 130-255). We observed that the benzoperimidines did not stimulate free radical formation, perhaps due to their poor substrate properties for NADH dehydrogenase.
Asunto(s)
Antraquinonas/síntesis química , Antineoplásicos/síntesis química , Pirimidinas/síntesis química , Animales , Antraquinonas/química , Antraquinonas/farmacología , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Ratones , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
Murine leukemia L1210 cells contain active glucosamine 6-phosphate synthase inhibited by N3-4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP). However, FMDP-peptides do not exhibit any cytotoxicity against these cells, HeLa S3 human cervical carcinoma cells, and LL2 murine Lewis lung carcinoma cells. It is suggested that the lack of cytotoxicity of FMDP-peptides, in spite of good drug uptake and the presence of target enzyme might be due to the poor rate of peptides cleavage by the intracellular peptidases.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Dipéptidos/farmacología , Animales , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/antagonistas & inhibidores , Humanos , Leucina/metabolismo , Ratones , Oligopéptidos/farmacología , Timidina/metabolismo , Células Tumorales Cultivadas , Uridina/metabolismoRESUMEN
The effect of the replacement of amino groups, attached to the anthraquinone ring in [(aminoalkyl)amino]-anthraquinones, by an amido function on DNA binding, cytotoxicity, and antileukemic activity has been studied. The corresponding 1,4-bis(aminoalkanamido)-9,10-anthracenediones have been synthesized and examined. It has been concluded that such modification does not exclude the DNA binding and cytotoxicity of mentioned compounds but decreases or abolishes the in vivo antileukemic activity.
Asunto(s)
Antraquinonas/síntesis química , Antineoplásicos , Animales , Antraquinonas/farmacología , Supervivencia Celular/efectos de los fármacos , ADN/metabolismo , Leucemia L1210/patología , Leucemia P388/tratamiento farmacológico , Ratones , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Eleven N-enamine derivatives of daunorubicin and of its 5-imino analogue as well as of doxorubicin have been synthesized and evaluated for antileukemic activity in vitro and in vivo. Comparison of biological activities of examined compounds with other enamine derivatives of daunorubicin, reported earlier by us, has indicated that the optimal activity is shown by N-(1-carboethoxypropen-1-yl-2)daunorubicin.