RESUMEN
The paper reports the cytotoxic activity of pyridylmethylene-2-indolinones previously described as cardiotonics and the synthesis of three analogs of the most potent cytotoxic agent. Some of these compounds could be useful, when associated with anthracyclines, to reduce the cardiotoxicity of these potent antitumor drugs.
Asunto(s)
Antineoplásicos/farmacología , Cardiotónicos/farmacología , Indoles/farmacología , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Cardiotónicos/síntesis química , Células HeLa/efectos de los fármacos , Humanos , Indoles/síntesis química , Pirimidinas/síntesis químicaRESUMEN
The synthesis of 5-chloro-3-pyridylmethylene-2-indolinone is reported. This compound was subjected to an in vivo cardiotonic assay with 10 analogs whose synthesis and in vitro cardiotonic activity were previously reported. All the compounds tested (except the 5-hydroxyindole derivative) showed significant positive inotropic activity. The 3-pyridyl derivative without substituents at the indole system was the most active of the whole series.
Asunto(s)
Cardiotónicos/farmacología , Indoles/farmacología , Piridinas/farmacología , Animales , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Indoles/síntesis química , Masculino , Milrinona , Contracción Miocárdica/efectos de los fármacos , Piridinas/síntesis química , Piridonas/farmacología , Relación Estructura-Actividad , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
In search of more potent compounds endowed with a cytotoxic activity, a new series of basic peptides was synthesized using solid-phase methods. All peptides were purified by preparative reverse-phase HPLC and characterized by electrospray mass spectrometry. The cytotoxic activity was determined in cultured HeLa cells. The hexadecapeptides 5 and 6 showed a 50% inhibition at the concentration of 30 micrograms/ml. The salmina and the polyamino acids of L-arginine, L-histidine and L-lysine, containing sixteen residues, were virtually inactive. This demonstrates that a specific peptide sequence is necessary to obtain a positive response in HeLa test.
Asunto(s)
Antineoplásicos/síntesis química , Péptidos/síntesis química , Secuencia de Aminoácidos , Antineoplásicos/farmacología , Células HeLa , Humanos , Datos de Secuencia Molecular , Péptidos/farmacologíaRESUMEN
Two new imidazo[2,1-b]thiazoles related to sulmazole were synthesized and subjected to an in vivo cardiotonic assay with 14 analog compounds which gave the best results in previously reported in vitro tests. The data obtained show that three substituents (3-pyridyl, 4-pyridyl and 2,5-dimethoxyphenyl group) are useful pharmacophoric groups in modulating the in vivo cardiotonic activity of the fused imidazoles considered.
Asunto(s)
Cardiotónicos/síntesis química , Imidazoles/síntesis química , Animales , Cardiotónicos/farmacología , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Contracción Miocárdica/efectos de los fármacosRESUMEN
Synthesis of four multimeric H-Lys-His-His-Arg-Lys-Lys-His-Arg-Lys-Arg-Lys-His-His-Lys-Arg-Lys-oH peptides containing two, four, eight and sixteen branches was carried out by solid phase utilizing a lysine core matrix. These multimeric peptides enhanced activity by inhibiting the colony-forming ability of HeLa cells, from twenty-four to fifty-six times in comparison with the monomeric form. Unexpectedly the peptide with only two-branched sequences showed the highest inhibitory activity.
Asunto(s)
Inhibidores de Crecimiento/síntesis química , Oligopéptidos/síntesis química , Secuencia de Aminoácidos , División Celular/efectos de los fármacos , Inhibidores de Crecimiento/química , Células HeLa , Humanos , Lisina/química , Datos de Secuencia Molecular , Oligopéptidos/farmacología , Relación Estructura-ActividadRESUMEN
The most widely-known anti-tumor drugs often induce marked immunosuppression which can give rise to one or more sepses. Anti-infection measures immediately applied can sometimes prove largely ineffective or even useless, the patient dying not as a result of the spread of the tumour but as a direct consequence of opportunistic infection. We postulate that antagonism between anti-tumour and antimicrobial drugs may also play an important part in this. By way of illustration of this hypothesis, we have studied the action of a number of known inhibitors of peptidoglycan synthesis and of DNA-gyrases on certain strains of Gram-positive and Gram-negative microorganisms cultured in medium containing various concentrations of some of the best-known anti-tumour antimetabolites. The experimental data show that antimicrobial and anti-tumour drugs can sometimes induce synergic or indifferent chemotherapeutic interactions with many bacteria, while in others the effect is antagonistic. In practice, the action of the drugs could lead to bacterial selectivity, which, in conjunction with immunosuppression and the presence of resistant strains, could favour the evolution of opportunistic infection.
Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Infecciones Oportunistas/microbiología , Aztreonam/farmacología , Cilastatina/farmacología , Combinación Cilastatina e Imipenem , Antagonismo de Drogas , Combinación de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada/farmacología , Enterococcus faecalis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/crecimiento & desarrollo , Humanos , Imipenem/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Serratia marcescens/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Teicoplanina/farmacologíaRESUMEN
The Knoevenagel reaction between 2-indolinones and 2-chloroindolaldehydes gave 3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones which were tested as potential antitumor agents on cultures of HeLa cells. 2-Chloro derivatives with at least one unsubstituted NH group, are promising candidates for further investigation.
Asunto(s)
Antineoplásicos/síntesis química , Indoles/síntesis química , Antineoplásicos/farmacología , Células HeLa/efectos de los fármacos , HumanosRESUMEN
Substances like imidazoles, benzimidazoles and also quinolines, whose chemical structure includes a heterocyclic nitrogen, are known to interfere with the microsomal oxidation and, in some cases, with the metabolism of drugs. Since chloroquine and primaquine exert this effect in vivo and in vitro, we studied the influence of other antimalarials (quinine and mepacrine) in mice with induced Ehrlich ascites tumour (EAT) to find out whether variations in oxygen consumption affected the course of the disease. In vitro data, obtained by a polarographic technique, indicate that primaquine and, in particular, mepacrine increase EAT-cell oxygen consumption, while in vivo data, obtained in mice injected with an inoculum of about 1 x 10(6) tumour cells per mouse, show that both drugs, but notably mepacrine, accelerate tumour growth, as monitored by Cox's statistical method for body weight, and lead to earlier death. In cases of existing neoplasia, therefore, the potentially toxic effects of certain antimalarials must be borne in mind.
Asunto(s)
Antimaláricos/farmacología , Carcinoma de Ehrlich/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Animales , Cloroquina/farmacología , Progresión de la Enfermedad , Femenino , Ratones , Trasplante de Neoplasias , Primaquina/farmacología , Quinacrina/farmacología , Quinina/farmacologíaRESUMEN
Synthesis of 2,6-Bis[bis(2-chloroethyl)amino]-4,8-dipiperidino-pyrimido [5,4-d]pyrimidine (DIP-C1) was carried out, and the new derivative showed cytotoxic activity comparable to other alkylating drugs on cultured P388 leukaemia cells and HeLa cells. The present paper reports the effects of DIP-C1 on respiration of Ehrlich ascites tumor cells and on survival of the mice implanted with Ehrlich ascites tumor cells. The compound showed a significant activity in both experimental models.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Carcinoma de Ehrlich/tratamiento farmacológico , Dipiridamol/análogos & derivados , Dipiridamol/farmacología , Animales , Antineoplásicos Alquilantes/síntesis química , Carcinoma de Ehrlich/metabolismo , Dipiridamol/síntesis química , Dipiridamol/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Células HeLa , Humanos , Leucemia P388 , Ratones , Consumo de Oxígeno/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
In connection with a previous research dealing with the antitumor activity of imidazo[2,1-b]-thiazole guanylhydrazones, this paper reports the synthesis of new derivatives which were tested for antitumor and positive inotropic activity. In most cases the cytotoxic data from the in vitro experiments (HeLa) were in agreement with the antitumor data in vivo (Ehrlich). The active compounds bear a phenyl ring at the 6 position. On the other hand, the most active cardiotonic agents were devoid of the phenyl ring.
Asunto(s)
Antineoplásicos/síntesis química , Cardiotónicos/síntesis química , Hidrazonas/síntesis química , Tiazoles/síntesis química , Animales , Antineoplásicos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Cardiotónicos/farmacología , Cloro , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa , Humanos , Hidrazonas/farmacología , Ratones , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
We synthesized eight peptides containing from three to twenty residues of arginine, lysine and histidine, using an automated synthetiser and Fmoc strategy. All peptides were purified by preparative reverse-phase HPLC and characterized by electrospay mass spectometry. Cytotoxic activity was assessed on HeLa cells. One peptide inhibited the colony-forming ability of tumor cells.
Asunto(s)
Fragmentos de Péptidos/farmacología , Secuencia de Aminoácidos , División Celular/efectos de los fármacos , Células HeLa/efectos de los fármacos , Humanos , Datos de Secuencia Molecular , Fragmentos de Péptidos/químicaRESUMEN
Several non catecholamine, non glycoside cardiotonic drugs have been described recently. New compounds include amrinone, sulmazole, milrinone and pimobendan. In an attempt to alleviate or prevent anthracycline toxicity, we have reported that these compounds reduce the negative effects of adriamycin, 4-epiadriamycin and esorubicin in isolated guinea pig atria. The present study reports the effects of a new cardiotonic agent: enoximone. Enoximone was administered after adriamycin (100 micrograms/ml) on the isolated and spontaneously beating atria, and on electrically driven left atria of guinea pig-in normodynamic and hypodynamic conditions. Exposure for 60 minutes to the antitumor drug causes a depression of contractile force (g) and its derivative versus time (dF/dt, as maximal rate of contractile force). The negative effects of adriamycin are antagonised by enoximone (100, 200 micrograms/ml).
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Cardiotónicos/uso terapéutico , Doxorrubicina/toxicidad , Enoximona/uso terapéutico , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Corazón/efectos de los fármacos , Animales , Función del Atrio Izquierdo/efectos de los fármacos , Interacciones Farmacológicas , Cobayas , Atrios Cardíacos/efectos de los fármacos , Técnicas In Vitro , Contracción Miocárdica/efectos de los fármacosRESUMEN
The in vitro activity of a chemotherapeutic agent, sulfimidazole (SIZ), obtained by combining two molecules belonging to groups of extremely different antibacterial drugs, p-aminobenzene sulfonamide and a derivative with a 5-nitroimidazole ring, was studied. In association with trimethoprim, SIZ induces an intense synergistic antibacterial effect on gram-negative and gram-positive aerobic microorganisms and Clostridia. The results show that, in SIZ, the activity of each starting molecule remains unchanged providing that its structure-action relationship is kept intact.
Asunto(s)
Antibacterianos/farmacología , Clostridium/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Nitroimidazoles/farmacología , Sulfonamidas/farmacología , Trimetoprim/farmacología , Sinergismo Farmacológico , Técnicas In Vitro , Factores de TiempoRESUMEN
It has been demonstrated that 18 alpha-glycyrrhetinic acid, 18 beta-glycyrrhetinic acid and glycyrrhizin effectively inhibit the inception and growth of skin tumours. Moreover, glycyrrhizin and its aglycone act on the growth and differentiation of mouse melanoma cells in culture. In this study we investigated the effect of glycyrrhizin, 18 alpha- and 18 beta-glycyrrhetinic acids on the evolution of Ehrlich ascites tumour in mice. A prolonged glycyrrhizin treatment proved to be effective in modifying the animals' survival pattern.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Ácido Glicirretínico/análogos & derivados , Animales , Carcinoma de Ehrlich/patología , División Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Femenino , Ácido Glicirretínico/farmacología , Ácido Glicirrínico , Goma Arábiga/farmacología , RatonesRESUMEN
We have investigated the effects of the H2 receptor antagonist roxatidine on the neuromuscular transmission by using the sciatic nerve-gastrocnemius muscle preparation of the rat in vivo. Roxatidine, administered by i.v. injection, potentiates the neuromuscular blockade induced by d-tubocurarine, pancuronium and aminoglycoside antibiotic, kanamycin. Moreover, the drug alone is capable of producing a blockade on the preparation stimulated at high frequency. The neuromuscular blockade induced by roxatidine is partially reversed by 4-aminopyridine but not by dimaprit.
Asunto(s)
Antagonistas de los Receptores H2 de la Histamina/farmacología , Unión Neuromuscular/efectos de los fármacos , Piperidinas/farmacología , 4-Aminopiridina/farmacología , Animales , Dimaprit/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inyecciones Intravenosas , Masculino , Músculo Esquelético/efectos de los fármacos , Bloqueantes Neuromusculares/farmacología , Ratas , Nervio Ciático/efectos de los fármacos , Tubocurarina/farmacologíaRESUMEN
A number of imidazo[2,1-b]thiazole guanylhydrazones, whose antitumor activity has already been described, were tested as potential cardiotonic agents. The guanylhydrazone of 2,3-dihydro-6-chloroimidazo[2,1-b]thiazole-5-carboxaldehyde (2a) was the most interesting compound showing both antitumor and cardiotonic activity.
Asunto(s)
Antineoplásicos/farmacología , Cardiotónicos/farmacología , Animales , Cobayas , Hidrazonas/farmacología , Imidazoles/farmacología , Técnicas In Vitro , Estructura MolecularRESUMEN
Recent clinical and toxicological studies have investigated the mineralcorticoid-like and hypertensive effects of liquorice, and we therefore set out to identify the active component responsible for these effects. We conducted a 30-day comparative analysis of glycyrrhizin and 18 beta-glycyrrhetinic acid and found that the latter causes significant variations both in systolic blood pressure and in the excretion in the urine of Ca++. The effects were fully reversible on suspension of treatment.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacología , Administración Oral , Animales , Calcio/orina , Ácido Glicirrínico , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The synthesis of potential differentiating agents related to hexamethylenebisacetamide (HMBA) is reported. 1,6-Bis(3,3-dimethyl-2-oxo-2,3-dihydroindol-1-yl)hexane (4) and 1,6-bis(4-carbamoyl-thiazol-2-yl)hexane (9) were not soluble enough to allow biological testing. For this reason the dipotassium salt (10) of 1,6-bis(4-carboxy-thiazol-2-yl)hexane (11) was prepared. The salt 10, tested in the human rhabdomyosarcoma cell line (RMZ) and in the murine Friend erythroleukemia cells (MEL), proved more cytotoxic than HMBA, but was devoid of differentiating activity. Compounds 4, 9, 10 and 11, tested on HeLa cells (in vitro) and on Ehrlich ascites (in vivo) did not show antitumor activity.
Asunto(s)
Acetamidas/síntesis química , Antineoplásicos/síntesis química , Acetamidas/farmacología , Animales , Antineoplásicos/farmacología , Carcinoma de Ehrlich/patología , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Trasplante de Células , Células HeLa , Humanos , Leucemia Eritroblástica Aguda/patología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Trasplante de Neoplasias , Rabdomiosarcoma/patología , Espectrofotometría Infrarroja , Células Tumorales CultivadasRESUMEN
A series of imidazo[2,1-b]thiazole adamantylthioureas (3a-f) was synthesized by reaction of the methylsulfanylethylamines 2a-f (prepared in turn from the hydroxymethylimidazo[2,1-b]thiazoles 1a-f and cysteamine) with 1-adamantylisothiocyanate. 1-Adamant-1-yl-3-[2-(6-chloro-2,3- dihydroimidazo[2,1-b]thiazol-5-ylmethylsulfanyl)ethyl] thiourea (3d) was significantly active.
Asunto(s)
Antineoplásicos/síntesis química , Tiazoles/síntesis química , Tiourea/análogos & derivados , Animales , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Leucemia P388/tratamiento farmacológico , Ratones , Tiazoles/farmacología , Tiourea/síntesis química , Tiourea/farmacología , Células Tumorales CultivadasRESUMEN
The synthesis of 6-anilinoimidazo[2,1-b]thiazoles, related to the well-known antitumor agent amsacrine, is reported. The cytotoxic activity of the new compounds was evaluated on HeLa cells. Compound 3a, the most closely related to amsacrine, was significantly active.