RESUMEN
The study of some 4-aroyl-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamides with a Saccharomyces cerevisiae mutagenicity test of increased sensitivity defined two of them, 4-(4-bromobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxam ide and 4-(4-fluorophenyl)-1-(2-chloroethyl)-1-nitrosohydrazine carboxamide as typical cytostatic agents. At concentrations of 2-5 microg/ml the substances kill up to 60%-70% of cells without having any detectable recombinogenic and mutagenic effects. At the same concentrations, lomustine, well known as a cytostatic reference, demonstrated recombinogenic and mutagenic activity on yeast cells. The advantage of the newly synthesized substances is that, in a certain concentration range, their biological activity is mainly cytotoxic without induction of recombinogenic and mutagenic events in surviving cells.
Asunto(s)
Antineoplásicos/toxicidad , Compuestos de Nitrosourea/toxicidad , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Carmustina/análogos & derivados , Hidrazinas/toxicidad , Lomustina/análogos & derivados , Pruebas de MutagenicidadRESUMEN
Six new analogues of nitrosoureas containing aroylhydrazine residue have been synthesized: (I) 4-(2-fluorobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide++ +; (II) 4-(4-bromobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxam ide; (III) 4-(4-hydroxybenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide+ ++; (IV) 4-(3-methoxybenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarbox amide; (V) 4-(4-methoxybenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarbox amide; (VI) 4-(4-fluorophenylacetyl)-1-(2-chloroethyl)-1-nitrosohydrazineca rboxamide. All six compounds showed a dose-dependent in vivo activity against leukaemias L1210 and P388. Compounds I and III were soluble in water. The antitumour effects were highly expressed in compound III, yielding a T/C% value of 402% in leukaemia P388, and in compound VI, 356% in leukaemia L1210.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Compuestos de Nitrosourea/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , RatonesRESUMEN
The complexes [Pt(bah)2X2], [Pt(NH3)(bah)Cl2].0.5H2O, [Pt(mbah)2X2], and [Pt(NH3)(mbah)Cl2] (bah = benzoic acid hydrazide, mbah = 3-methoxybenzoic acid hydrazide; X = Cl, Br, I) have been prepared and characterized by elemental analysis, electric conductivity, IR, 1H NMR, and electronic spectra. A cis-square planar structure with hydrazide ligands coordinated via the NH2-groups has been proposed for these complexes. The complexes have shown a growth-inhibitory effect against Friend leukemia cells in culture comparable to that of the antitumor drug cisplatin.
Asunto(s)
Antineoplásicos/síntesis química , Benzoatos/química , Compuestos de Platino/síntesis química , Ácido Vanílico/análogos & derivados , Antineoplásicos/farmacología , Benzoatos/farmacología , Ácido Benzoico , División Celular/efectos de los fármacos , Cisplatino/farmacología , Conductividad Eléctrica , Virus de la Leucemia Murina de Friend , Leucemia Eritroblástica Aguda/patología , Espectroscopía de Resonancia Magnética , Compuestos de Platino/farmacología , Espectrofotometría Infrarroja , Análisis Espectral , Células Tumorales Cultivadas , Ácido Vanílico/química , Ácido Vanílico/farmacologíaRESUMEN
Five different representatives (I-V) of a new class of bifunctional alkylating agents, the 4-aroyl-1-nitrosohydrazinecarboxamides ("nitrososemicarbazides"), were evaluated for their potential interaction with DNA and for their cytotoxic activity in vitro to O6-alkylguanine-DNA alkyltransferase-positive (Mer+) and -negative (Mer-) human cell lines. The HeLa MR cell line (Mer-) showed up to 20-fold higher sensitivity at IC50 (dose that inhibits colony formation by 50%) to agents I-V than did the HeLa S3 cell line (Mer+) in a colony-formation assay. These data were compared to those obtained by treatment of the two cell lines with carmustine, a currently used antitumor drug. In Mer+ cells comparable results to those with carmustine were obtained with compounds III, IV and V; in Mer- cells compounds I and II showed nearly the same effects as carmustine. Whether compounds I-V produce DNA strand breaks and/or DNA-protein cross-links was investigated using an alkaline filter elution technique. In this assay all compounds produced DNA single-strand breaks; no correlation could be detected between the strand breakage frequency and cytostatic, mutagenic and antitumor activity.
Asunto(s)
Metiltransferasas/metabolismo , Compuestos Nitrosos/toxicidad , Compuestos de Nitrosourea/toxicidad , Semicarbacidas/toxicidad , Carmustina/toxicidad , Línea Celular , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Pruebas de Mutagenicidad , Compuestos de Nitrosourea/química , O(6)-Metilguanina-ADN Metiltransferasa , Ensayo de Tumor de Célula MadreAsunto(s)
Antineoplásicos/síntesis química , Compuestos de Nitrosourea/síntesis química , Compuestos Organofosforados/síntesis química , Fosfinas/síntesis química , Animales , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Leucemia L1210/patología , Leucemia P388/patología , Compuestos de Nitrosourea/farmacología , Compuestos Organofosforados/farmacología , Fosfinas/farmacología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Five experimental anti-leukemic agents, 1-(2-chloroethyl)-4-arylacyl-1-nitrososemicarbazides, were synthesized and tested for genotoxicity in the Salmonella/mammalian microsome assay. No strong mutagenic activity could be detected when tested with the S. typhimurium TA98. A clear dose-dependent base-pair-substitution mutagenic activity was observed with each compound when the tester strain TA100 was used with or without metabolic activation. The genotoxicity of the unsubstituted substance was similar to that of the known mutagenic cytostatic drugs, lomustin and carmustin, and was stronger than the mutagenicity of each substituted derivative.
Asunto(s)
Antineoplásicos/farmacología , Mutágenos/farmacología , Compuestos Nitrosos/farmacología , Semicarbacidas/farmacología , Microsomas/efectos de los fármacos , Pruebas de Mutagenicidad/métodos , Salmonella/efectos de los fármacos , Relación Estructura-Actividad , Urea/farmacologíaRESUMEN
1-Methyl-1-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, 1,1-di-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide and 1,1-di-(2-bromoethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, which are a novel class of nitrosoureas containing hydrazinomustard residue, have been synthesized. A dose-dependent antitumour activity was found with the three tested compounds.