RESUMEN
In the crystal structure of the title compound, 4-(3,3-dimethyl-1-triazeno)benzamide, C9H12N4O, (2), the N = N double bond [1.282 (8) A] is 0.030 A shorter than the N--N single bond [1.312 (8) A], but both bonds are shorter than an isolated N--N single bond suggesting that there is double-bond character in each N--N bond, although it is unequally distributed. The molecule adopts a trans geometry around the N = N bond, but there is a significant deviation from planarity between the benzene ring and the plane of the triazene moiety. Compound (2) forms chains in the solid state in which the molecules are linked by C = O...H--N hydrogen bonds between carbamoyl groups. These chains are cross-linked into sheets by hydrogen bonding between the second N--H moiety and triazene units in adjacent chains.
Asunto(s)
Antineoplásicos/química , Triazenos/química , Cristalografía , Enlace de Hidrógeno , Modelos Moleculares , Estructura MolecularRESUMEN
An excellent correlation has been shown to exist between the 15N NMR chemical shifts of a series of aryl nitrogen mustards and the Hammett constant, sigma, which is much improved by the use of sigma-. These chemical shifts also correlate well with the hydrolysis rates of the compounds in 50% aqueous acetone at 66 degrees C and their alkylation of 4-(4'-nitrobenzyl)pyridine under similar conditions. Thus 15N NMR is a straightforward and material-conserving method for estimating the relative stabilities of aryl nitrogen mustards.
Asunto(s)
Compuestos de Mostaza Nitrogenada/química , Estabilidad de Medicamentos , Hidrólisis , Cinética , Espectroscopía de Resonancia Magnética , Isótopos de NitrógenoRESUMEN
Alkylation of DNA by the nitrogen mustard bis(2-chloroethyl)methylamine (mechlorethamine; HN2) gave four principal products, derived by mono-alkylation of guanine at N-7 and adenine at N-3 and by cross-linking of guanine to guanine or guanine to adenine at these positions. These products were isolated by hydrolysis from DNA at neutral pH, followed by ion-exchange chromatography on SP-Sephadex and reversed phase chromatography on ODS. They were characterized by identification with products from the reaction of nitrogen mustard with adenine or deoxyguanylic acid, and by their UV, mass, and proton magnetic resonance spectra.
Asunto(s)
ADN/química , Mecloretamina/química , Alquilación , Animales , Cromatografía por Intercambio Iónico , Aductos de ADN/química , Aductos de ADN/aislamiento & purificación , Salmón , Espectrofotometría UltravioletaRESUMEN
In exploring the structural features which determine the antitumor activity of 2,4,6-tris-[(hydroxymethyl)methylamino]-1,3,5-triazine (trimelamol, 1), we have synthesized analogues in which the methyl groups have been replaced by the electron-withdrawing substituents 2,2,2-trifluoroethyl (5), propargyl (13), and cyanomethyl (15) via the respective tris(alkylamino)triazines 3, 12, and 14. Three mono[(hydroxymethyl)amino]triazines (4, 7, and 10) were also prepared. All the new tris(hydroxymethyl) derivatives showed cytotoxicities toward a variety of experimental rodent and human ovarian tumor cell lines similar to those shown by 1, the cyanomethyl analogue (15) having the most favorable profile. Mono(hydroxymethyl) derivatives (4 and 7) were ca. one-third as toxic. The new tris(hydroxymethyl) analogues were more stable to aqueous hydrolysis than was 1. Half-life (pH 7.5) values were, for 1, 120 min, for 5, 690 min, for 13, 450 min, and for 15, 275 min, but at pH 2.0, 15 (t1/2 350 min) was the most stable. This cyanomethyl analogue was also the most water-soluble, being comparable to 1 whereas 5 and 13 were poorly soluble.
Asunto(s)
Antineoplásicos/síntesis química , Triazinas/química , Animales , Antineoplásicos/uso terapéutico , Estabilidad de Medicamentos , Semivida , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Leucemia L1210/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Estructura Molecular , Plasmacitoma/tratamiento farmacológico , Ratas , Solubilidad , Relación Estructura-Actividad , Triazinas/uso terapéutico , Células Tumorales CultivadasRESUMEN
The content of the phospholipid metabolites, phosphocholine, phosphoethanolamine, glycerophosphorylcholine and glycerophosphorylethanolamine was measured in chemical extracts from 46 human breast carcinoma using 31P NMR spectroscopy. Some patients had received therapy prior to tumour resection. The data were therefore stratified into two groups: (i) all tumours; and (ii) untreated tumours. Three indices of tumour proliferation i.e., mitotic index, Ki67 and S-phase fraction were determined on tissue from the same tumours and were found not to correlate with the content of any of these metabolites. In addition oestrogen-receptor status and density, tumour grade and DNA ploidy were obtained on some tumours. The phosphocholine content was higher in high grade tumours when compared with low grade tumours. There was no apparent relationship between DNA ploidy and the content of any of these metabolites. Glycerophosphorylcholine content of oestrogen-receptor positive tumours correlated with receptor density. However, there was no significant difference between receptor positive and negative tumours in the content of any of the phospholipid metabolites measured.
Asunto(s)
Neoplasias de la Mama/química , Carcinoma Ductal de Mama/química , Fosfolípidos/análisis , Aneuploidia , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , ADN de Neoplasias/análisis , Etanolaminas/análisis , Femenino , Glicerilfosforilcolina/análisis , Humanos , Antígeno Ki-67 , Espectroscopía de Resonancia Magnética , Índice Mitótico , Proteínas de Neoplasias/análisis , Proteínas Nucleares/análisis , Fosfatidiletanolaminas/análisis , Fosforilcolina/análisis , Pronóstico , Receptores de Estrógenos/análisis , Fase S , Extractos de TejidosRESUMEN
The molecular structures of the title compounds have been determined by X-ray crystallographic methods. The analyses revealed differences in the geometry, and by inference the bond delocalization in these two triazenes owing to the presence in the 1-oxide structure of an N-O bond. The geometries are compared to the crystal structures of the isomeric 3-oxides [Kuroda & Wilman (1985). Acta Cryst. C41, 1543-1545; Neidle, Webster, Kuroda & Wilman (1987). Acta Cryst. C43, 674-676] which shows the dominance of an alternative tautomeric equilibrium for the triazene groups.
Asunto(s)
Óxidos N-Cíclicos/química , Triazenos/química , Triazinas/química , Gráficos por Computador , Dacarbazina/química , Conformación Molecular , Estructura Molecular , Difracción de Rayos X/métodosRESUMEN
The synthesis of two novel drugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoic acid (7) and 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoic acid (8) is described here. They are the active drugs of two prodrugs (9 and 10) designed for use as anti-cancer agents. The prodrugs (9, 10 and 11) were made as a series of compounds which are bifunctional alkylating agents in which the activating effect of the ionized carboxyl function is masked through an amide bond to a glutamic acid residue. These relatively inactive prodrugs were designed to be activated to their corresponding alkylating agent active drugs (7, 8 and 12 respectively) at a tumour site by prior administration of a monoclonal antibody conjugated to a bacterial enzyme. This system is called antibody-directed enzyme prodrug therapy (ADEPT). The chemical half-lives of the prodrugs and their active drugs were measured in order to determine their relative reactivities. The half-lives ranged from 21 to 324 min for the active drugs and from 42 to 1158 min for the prodrugs. The viability of two different tumour cell lines was monitored with each active drug and prodrug. The IC50 values varied from 65 to 625 microM for the active drugs: no IC50 values could be obtained for the prodrugs, using a rapid incubation procedure. Each in vitro technique demonstrated the ability of the glutamic acid moiety to deactivate the drugs, forming effective prodrugs.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacocinética , Benzoatos/farmacocinética , Enzimas/inmunología , Compuestos de Mostaza Nitrogenada/farmacocinética , Profármacos/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bacterias/enzimología , Benzoatos/síntesis química , Benzoatos/farmacología , Coriocarcinoma/tratamiento farmacológico , Coriocarcinoma/metabolismo , Coriocarcinoma/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Enzimas/metabolismo , Glutamatos/síntesis química , Glutamatos/farmacocinética , Glutamatos/farmacología , Semivida , Humanos , Compuestos de Mostaza Nitrogenada/síntesis química , Compuestos de Mostaza Nitrogenada/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Células Tumorales CultivadasRESUMEN
Trimelamol is an analogue of hexamethylmelamine and pentamethylmelamine which does not require metabolic activation and is sufficiently soluble to allow parenteral administration. A Phase I trial has been performed at the Royal Marsden Hospital in which two schedules of administration have been evaluated, a single i.v. infusion repeated every 3 weeks and 3 daily doses repeated every 3 weeks. Pharmacokinetic analysis was performed at all dose levels on both schedules and a linear correlation was demonstrated between dose and area under the curve. Myelosuppression was dose limiting for single dose administration with a maximum tolerated dose of 2400 mg/m2. Median leukocyte nadirs at 1800, 2100, and 2400 mg/m2 were 3.2, 2.6, and 1.5 x 10(9)/liter. Thrombocytopenia and anemia also occurred but were not dose limiting. Doses greater than 1500 mg/m2 caused WHO grade 3 nausea and vomiting but no acute sedation. Three day administration appeared to be less myelosuppressive, giving a maximum tolerated dose of 1000 mg/m2. Median leukocyte nadirs at 800, 900, and 1000 mg/m2 daily for 3 days were 3.0, 2.3, and 1.5 x 10(9)/liter. Nonhematological toxicities were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in ovarian cancer has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Triazinas/administración & dosificación , Triazinas/efectos adversos , Triazinas/farmacocinética , Vómitos/inducido químicamenteRESUMEN
A series of derivatives of the ribonucleotide reductase inhibitory anti-tumour agent 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY), including all the methyl analogues, have been synthesised. IMPY itself caused 50% inhibition of L1210 tumour-derived ribonucleotide reductase at a concentration of 0.39 mM, comparable with enzyme obtained from other sources. The analogues proved to be no better than IMPY, either as inhibitors of this enzyme or of the growth of L1210 cells in vitro. No correlation was apparent between biological activity and position of substitution.
Asunto(s)
Antineoplásicos/síntesis química , Pirazoles/síntesis química , Ribonucleótido Reductasas/antagonistas & inhibidores , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione (1) is a strong competitive inhibitor of human placental aromatase (Ki = 1.1 microM; testosterone as substrate) that, unlike the structurally related aromatase inhibitor aminoglutethimide (2), is not also an inhibitor of the cholesterol side-chain cleavage enzyme desmolase. An improved synthesis of 1 is described, which was readily adapted to the preparation of homologues in a series of 3-alkyl-3-(4-pyridyl)-piperidine-2,6-diones (6-13). Alkylation of 1 afforded a second series, comprising 1-alkyl-3-ethyl-3-(4-pyridyl)-piperidine-2,6-diones (14-23). Inhibitory activity toward aromatase was maximal in both series for the octyl derivatives. Respective Ki values for the competitive inhibition exerted by the 3-octyl (12) and the 1-octyl (21) analogues with testosterone as substrate were 0.09 and 0.12 microM. The compounds 1, 2, 12, and 21 differed in their relative potencies as inhibitors of the aromatization of testosterone and androstenedione. Respective Ki values were as follows: for 1, 1.1 and 14 microM (ratio 12.7); for 2, 0.6 and 1.8 microM (3); for 12, 0.09 and 0.20 microM (2.2); and for 21, 0.12 and 0.48 microM (4).
Asunto(s)
Aminoglutetimida/análogos & derivados , Antineoplásicos/farmacología , Inhibidores de la Aromatasa , Alquilación , Aminoglutetimida/farmacología , Cromatografía Líquida de Alta Presión , Matemática , Relación Estructura-ActividadRESUMEN
Spectrophotometric studies have been undertaken of the interaction of various iron-based systems with the anti-tumour agent, 2,3-dihydro-1H-imidazo(1,2-b)pyrazole (IMPY, NSC (51143), a ribonucleotide reductase inhibitor. No evidence was obtained of direct complexation in aqueous media at 25 degrees C between IMPY and Fe2+ (aq) (pH 1.5-6.8) or Fe3+ (aq) (pH 1.0-3.5), nor with a mu-oxo-bridged iron dimer (Fe--O--Fe) system. There was definitive spectral evidence of complexation of IMPY with protoporphyrin IX iron (II) at pH 7.4 and 12.9 both in the absence and presence of carbon monoxide bound at the haem-iron site. Binding of IMPY to protoporphyrin IX iron (III), in contrast, was not detected. Binding between IMPY and various iron sites important in biochemistry is discussed briefly, especially in relation to the structural properties of IMPY (from X-ray data) and the Fe--O--Fe bridge system in ribonucleotide reductase and model systems. The difficulties of the use of free heterocyclic nitrogenous bases in medicinal chemistry are discussed.
Asunto(s)
Antineoplásicos/metabolismo , Hemo/metabolismo , Hierro/metabolismo , Pirazoles/metabolismo , Ribonucleótido Reductasas/antagonistas & inhibidores , EspectrofotometríaAsunto(s)
Antineoplásicos/metabolismo , Neoplasias/tratamiento farmacológico , Altretamina/metabolismo , Mostaza de Anilina/metabolismo , Animales , Antineoplásicos/efectos adversos , Compuestos Azo/metabolismo , Biotransformación , Química Farmacéutica , Ciclofosfamida/metabolismo , Dacarbazina/metabolismo , Evaluación de Medicamentos , Femenino , Galactosidasas/metabolismo , Glucuronosiltransferasa/metabolismo , Humanos , Imidazoles/metabolismo , Hígado/enzimología , Masculino , Náusea/inducido químicamente , Neoplasias/metabolismo , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Relación Estructura-Actividad , Temozolomida , Vómitos/inducido químicamenteRESUMEN
Comprehensive pharmacokinetic studies could realise a greater potential for the antitumour agent triethylenethiophosphoramide (ThioTEPA), and these would be aided by the development of a selective and sensitive assay. After extraction of ThioTEPA and its metabolite, triethylenephosphoramide (TEPA), from plasma using Sep-Pak C18 cartridges, the compounds were separated by capillary chromatography, detected using a nitrogen detector and quantified by reference to an internal standard, hexaethylphosphoramide. The limits of sensitivity were 1-5 ng/ml. Analytical recoveries were 74 and 95%, for TEPA and ThioTEPA, respectively, in the therapeutic range. At similar concentrations, extents of protein binding, determined by ultrafiltration, were not significant. Preliminary investigations of the elimination of ThioTEPA show that drug loss occurs more quickly in mice than in humans and in both species the metabolite is extensively recycled.
Asunto(s)
Azirinas/sangre , Tiotepa/sangre , Trietilenofosforamida/sangre , Animales , Cromatografía de Gases , Femenino , Semivida , Humanos , Cinética , Ratones , Nandrolona/análogos & derivados , Nandrolona/farmacología , Unión Proteica , Especificidad de la Especie , Ultrafiltración , gammaglobulinas/metabolismoRESUMEN
The in vivo antitumor activity and in vitro metabolic dealkylation have been measured for an homologous series of 3-alkyl-1-(4-carbamoylphenyl)-3-methyltriazenes and have been compared with their partition coefficients. This investigation has shown that the extent of oxidative metabolism in vitro and the antitumor activity in vivo of these compounds are dependent upon hydrophobicity. These findings provide confirmation for the relationship between metabolism and antitumor activity for aryldialkyltriazenes.
Asunto(s)
Antineoplásicos/síntesis química , Triazenos/síntesis química , Animales , Cromatografía Líquida de Alta Presión , Femenino , Linfoma/tratamiento farmacológico , Matemática , Ratones , Ratones Endogámicos CBA , Microsomas Hepáticos/metabolismo , Relación Estructura-Actividad , Triazenos/uso terapéuticoAsunto(s)
Antineoplásicos/farmacología , Compuestos Azo/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Antineoplásicos/aislamiento & purificación , Compuestos Azo/aislamiento & purificación , Benzoatos/aislamiento & purificación , Benzoatos/farmacología , Fenómenos Químicos , Química , Semivida , Humanos , Isomerismo , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
An homologous series of water-soluble, chemically stable analogues of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) has been prepared with activity comparable to DTIC in an experimental tumor system. The antitumor activity of this series of 3-alkyl-1-(4-carboxyphenyl)-3-methyltriazenes rapidly diminishes at alkyl chain lengths greater than pentyl. Partition coefficients were determined, but no relationship between these and antitumor activity could be established.