RESUMEN
Despite current optimal treatment, the morbidity and mortality of coronary heart disease remain significant worldwide and open the way for the development of novel cardioprotective therapies. In the last two decades, a remarkable scientific effort has focused on the limitation of infarct size. Important input from experimental studies has led the way in this direction. However, clinical and preclinical results using various cardioprotective strategies to attenuate reperfusion injury have generally not been applicable for every day clinical practice. Protection of the ischemic myocardium is known to occur as a result of ischemic preconditioning (PC), in which repetitive brief periods of ischemia protect the heart from a subsequent prolong ischemic insult. Although PC is a powerful form of protection, it is of limited clinical application for obvious ethical and practical reasons. Another endogenous form of cardioprotection, similar to PC but applicable at the time of reperfusion, termed postconditioning (PostC), has been recently described. Short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied at the onset of reperfusion, reduce the infarct size and coronary artery endothelial dysfunction. At present, pharmacological PC and PostC are possible alternative methods that may substitute pharmaceutical treatments the short ischemic insults. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. We summarize the recent research efforts on novel therapeutic strategies and on the design of new compounds, based on the accumulated knowledge of the ligands, receptors and intracellular signaling pathways of PC and PostC.
Asunto(s)
Cardiotónicos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Cardiotónicos/química , Diseño de Fármacos , Humanos , Precondicionamiento Isquémico , Estructura Molecular , Infarto del Miocardio/prevención & controlRESUMEN
The synthesis of a series of new N-OMe fluoro-indoles with melatoninergic activity in the Xenopus melanophore assay is described. All of the 4-F substituted compounds, 22a-e and 25a,b, were antagonists on the clonal Xenopus melanophore line. Conversely, the 5-F substituted analogs (15a-e) did not share the same pharmacological profile, as two of them, compounds 15d (R=c-C(3)H(5)) and 15e (R=c-C(4)H(7)), exhibited a weak agonistic and partial agonistic activity, respectively, whilst the other three (15a-c) were all agonists. It seems that in this case the nature of the response (agonist or antagonist activity) is solely dependent on the shape of the R group.
Asunto(s)
Indoles/síntesis química , Melanóforos/efectos de los fármacos , Melatonina/agonistas , Melatonina/antagonistas & inhibidores , Animales , Diseño de Fármacos , Indoles/farmacología , Relación Estructura-Actividad , XenopusRESUMEN
A facile synthesis of the C4-substituted isoquinolines 5a-c and 6a-c is described. Commercially available 4-bromoisoquinoline is converted to the alpha,beta-unsaturated esters 8 and 10 on treatment with the appropriate acrylate ester under Heck reaction conditions. The saturated amides 5a-c were obtained from the reaction of ester 9 with the requisite primary amine. Similarly the unsaturated analogues 6a-c were prepared by reacting ester 10 with the appropriate amine. The cytotoxicity of the target molecules was evaluated in two tumour cell lines in vitro. Two compounds, 6b and 6c, showed sufficient activity in the human non-small cell lung cancer line NSCLC-N16-L16 to be worthy of further study.
RESUMEN
Tricyclic analogs of melatonin with alkyl and cycloalkyl moieties in the beta position of the ethylamido chain have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores. The introduction of two methyl groups in the beta position of the side-chain of the methoxyl-substituted ligands induces a synergistic effect in agonist potency, which, importantly, is maintained after the methoxyl substituent is removed. The presence of more bulky beta-substituents, regardless of the size of the R group, seems to lead to antagonism.
Asunto(s)
Indoles/síntesis química , Melanóforos/efectos de los fármacos , Melatonina/síntesis química , Animales , Técnicas de Cultivo , Interacciones Farmacológicas , Indoles/farmacología , Melatonina/farmacología , Relación Estructura-Actividad , Xenopus laevisRESUMEN
A series of new melatonin analogues have been synthesized. Interestingly, two of the new compounds, 11c and 11e, which did not show any appreciable affinity for the melatonin receptor, were found to be potent inhibitors of lipid peroxidation in rat liver microsomes. Analogue 11c, in particular, is a better antioxidant than melatonin.
Asunto(s)
Antioxidantes/síntesis química , Indoles/síntesis química , Peroxidación de Lípido/efectos de los fármacos , Melatonina/análogos & derivados , Animales , Antioxidantes/química , Antioxidantes/farmacología , Femenino , Indoles/química , Indoles/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Ratas , Ratas Endogámicas F344 , Receptores de Superficie Celular/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores de Melatonina , Relación Estructura-ActividadRESUMEN
We report the synthesis and biological evaluation of a series of new tricyclic analogs of the hormone melatonin, which act as probes of the constraints at the hormone's receptor site with regard to the lower N1-C2 region of the indole moiety of melatonin. Three of the new compounds, N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)ethyl]acetamide (9), and the respective propionamide 10 and butyramide 11, are as potent as melatonin in the Xenopus laevis melanophore model.
Asunto(s)
Indoles/síntesis química , Melatonina/análogos & derivados , Animales , Indoles/farmacología , Ligandos , Melanóforos/efectos de los fármacos , Melatonina/agonistas , Melatonina/antagonistas & inhibidores , Xenopus laevisRESUMEN
It is now well known that treatment of tumors, especially non-small-cell lung cancer (NSCLC), remains limited and it is urgent to develop strategies that target tumor cells and their genetic features. In this regard, our work is about genetic modifications arising in an in vitro NSCLC cell line after treatment with a chemical substance, methyl 4-methoxy-3-(3-methyl-2-butenoyl) benzoate (VT1). First, we showed that VT1 induces arrest of proliferation by blocking cells in the G1 phase of the cell cycle. Second, we use "differential display" strategy to clarify the genetic mechanisms involved in this proliferation arrest. A novel mRNA, NY-CO-1 (New-York Colon 1), of unknown function showed up-regulated expression after treatment. Application of "antisense" strategy confirmed this novel mRNA induction was effectively linked to growth arrest. Therefore, these data provide new information about mechanisms participating in arrest of proliferation of tumor cells and open new ways of treatment to target tumor growth.
Asunto(s)
Alquenos/farmacología , Antígenos de Neoplasias/genética , Antineoplásicos/farmacología , Benzoatos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/genética , Antígenos de Neoplasias/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Proteínas de Unión al ADN/análisis , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Proteínas de Transporte Nucleocitoplasmático , Oligonucleótidos Antisentido/farmacología , ARN Mensajero/metabolismo , Proteína de Replicación A , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
The antiretroviral and anti-oxidant profile of a series of new C-2 and C-7 substituted benzo[b]furans was explored by employing well established antiviral and antioxidant protocols. The most potent antioxidant compound tested was analog 7, which bears an OH at C-7 and a benzoyl group at C-2. In the influenza A type H3N2 virus screens analog 8a was almost five-fold more active than its counterparts and equipotent to rimantadine and amantadine. In the influenza B screening all of the new compounds tested were at least ten-fold more active than the control drug amantadine. The anti-HIV screening, using acutely infected MT-4 cells, showed that compound 8f (n = 4), was fifteen-fold more active than its monomer congeners, 8a and 8c, d and almost five-fold more potent than monomer 8b and dimer 8f (n = 3).
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Benzofuranos/síntesis química , Benzofuranos/farmacología , Retroviridae/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Efecto Citopatogénico Viral/efectos de los fármacos , Femenino , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/química , Peroxidación de Lípido/efectos de los fármacos , Orthomyxoviridae/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
6H-Isoindolo[2,1-a]indoles (5, 7, 10, 13), 5,6-dihydroindolo[2, 1-a]isoquinolines (20, 21), and 6,7-dihydro-5H-benzo[c]azepino[2, 1-a]indoles (23, 25, 27, 30) have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human mt(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. The 2-methoxyisoindolo[2, 1-a]indoles (7a-d) showed much higher binding affinities than the parent isoindoles (5a-e), and whereas 7a-c were agonists in the functional assay, 7d and 5a-e were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10a-d) showed reduced binding affinities compared to their methoxy analogues, while the 5-chloro derivative 13 showed a considerable reduction in binding affinity and potency compared to 7a. The 10-methoxy-5,6-dihydroindolo[2, 1-a]isoquinolines (21a-c) had higher binding affinities than the corresponding parent indoloisoquinolines (20a-c) in the human receptor subtypes, and the parent compounds were antagonists whereas the 10-methoxy derivatives were agonists in the functional assay. The N-cyclobutanecarbonyl derivatives of both the parent (20d) and 10-methoxyl (21d) series had similar binding affinities and were both antagonists with similar potencies. The 11-methoxy-6, 7-5H-benzo[c]azepino[2,1-a]indoles (25a-d) had higher binding affinities than the corresponding parent compounds (23a-d) at the MT(2) receptor but similar affinities at the mt(1) site; all of the compounds were antagonists in the functional assay. Changing 11-methoxy for 11-ethoxy decreased the binding affinity slightly, and this was more evident at the MT(2) receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT(2) receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT(2) receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt(1) and MT(2) melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT(2) receptor, while 25c is an MT(2)-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.
Asunto(s)
Indoles/síntesis química , Melatonina/metabolismo , Receptores de Superficie Celular/agonistas , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Células 3T3 , Animales , Unión Competitiva , AMP Cíclico/metabolismo , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Isoindoles , Ratones , Pigmentos Biológicos/metabolismo , Ensayo de Unión Radioligante , Receptores de Melatonina , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-Actividad , Xenopus laevisRESUMEN
3-[(2-Methyl-1H-3-indolyl) methyl]-4-aryl-4, 5-dihydro-1H-1,2,4-triazole-5-thiones 6a-c and their respective N-¿5-[2-methyl-1H-3-indolyl) methyl]-1,3,4-thiadiazol-2-yl¿-N-arylamines 7a,b have been prepared. The antidepressant profile of 6a,c and 7a was studied on mice with respect to that of the analogous 3-(1H-1-indolylmethyl)-4-aryl-4,5-dihydro-1H-1,2,4-triazole-5-thio nes 1a-c and the respective N-¿5-[(2-methyl-1H-3-indolyl) methyl]-1,3,4-thiadiazole-2-yl¿-N-arylamines 2a-c, the synthesis and antimicrobial potency of which we have recently reported. Behavioral effects, induced by the members of both series, in conjunction with their activity in some specific tests (forced swim, pentetrazole convulsions) on mice, show that these derivatives cross the blood-brain barrier and could develop an antidepressant activity comparable to that of imipramine. Blood-brain barrier penetration is also supported by the lipophilicity data obtained for all analogs.
Asunto(s)
Antidepresivos/síntesis química , Tiadiazoles/síntesis química , Triazoles/síntesis química , Animales , Barrera Hematoencefálica , Masculino , Ratones , Ratones Endogámicos BALB C , Solubilidad , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
The increasing clinical importance of drug-resistant bacterial pathogens has lent additional urgency to microbiological and antibacterial research. New indolic derivatives of triazoles, thiadiazoles and their respective open-chain thiosemicarbazides were evaluated for antibacterial and antifungal activity. The microorganisms used were the Gram-negative bacteria Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853, the Gram-positive bacteria Staphylococcus aureus ATCC 25923 and Bacillus subtilis BBL 12084 and the yeasts Candida and Saccharomyces cerevisiae ATCC 2366. The most potent compounds were indole derivatives (12a-c) bearing 1,2,4-triazo-thien-5-yl moiety, which exhibit interesting antibacterial and antifungal activities.
Asunto(s)
Antiinfecciosos/síntesis química , Indoles/síntesis química , Tiadiazoles/síntesis química , Triazoles/síntesis química , Antibacterianos , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Indoles/farmacología , Pruebas de Sensibilidad Microbiana , Tiadiazoles/farmacología , Triazoles/farmacologíaRESUMEN
A series of new ether lipid-3'-azido-3'-deoxythymidine (AZT) conjugates (11a-g) were synthesized and evaluated for anti-HIV activity. The effect of chirality on the antiviral activity was examined through the synthesis of AZT conjugates bearing alkoxypropanols in the lipid portion of the molecule (11a-d). In addition, the long alkyl chain of alkoxyethyl ether lipid-AZT analogs was replaced with aromatic groups (11e-g), and the effect of this structural modification on activity is reported. The results of the biological tests indicate that analogs with a methyl group alpha to the phosphate moiety (11c,d) exhibit a marked degree of stereoselectivity with regard to their anti-HIV activity. Also, replacement of the long alkyl chain with aromatic groups in the oxyalkyl ether phospholipid-AZT conjugates leads to substantially more potent compounds (11e-g) with an anti-HIV activity comparable to that of AZT.
Asunto(s)
Antivirales/síntesis química , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Retroviridae/efectos de los fármacos , Zidovudina/análogos & derivados , Zidovudina/síntesis química , Alquilación , Antivirales/química , Antivirales/farmacología , Línea Celular , Humanos , Espectroscopía de Resonancia Magnética , Fosfolípidos , Relación Estructura-Actividad , Linfocitos T , Zidovudina/farmacologíaRESUMEN
We have examined the effect of a series of substituted imidazothioxanthones on the stability of an intermolecular DNA triple helix by DNase I footprinting. We find that several of these compounds promote the formation of a complex between T5C5 and the target site A6G6.C6T6, suggesting that they bind specifically to triplex DNA. The only inactive derivative lacked a protonatable function in the side chain, suggesting that this is an essential feature for triplex stabilization. These compounds, which are amongst the first triplex-binding ligands which possess an uncharged chromophore, are selective for the T.AT rather than the C+.GC triplet.
Asunto(s)
ADN/efectos de los fármacos , Xantenos/farmacología , Xantonas , ADN/química , Huella de ADN , Desoxirribonucleasa I/metabolismo , Xantenos/químicaRESUMEN
Two series of phosphodiester ether lipid analogs with (N-methylmorpholino)ethyl or (N-methylpiperidino)ethyl polar head groups and long aliphatic or alkoxyethyl chains in the nonpolar portion of the molecule were synthesized as potential antineoplastic agents. The cytotoxic activity of these compounds (9-19) was evaluated in vitro against a panel of six human tumor xenografts and in two biochemical, mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Analogs 13, 14, 17, and 19 showed activity in the in vitro tests. Specifically, 14 and 17 were more active than the reference compound hexadecylphosphocholine (Miltefosine, He-PC) while 13 and 19 possessed activity similar to that of the control. Of the analogs tested the one with the highest potency and least toxicity (17) has an N-methylpiperidino head group and a C16 alkyl chain. In the mechanism-based tests 11 showed weak inhibitory activity in the cdc25 phosphatase screen.
Asunto(s)
Antineoplásicos/farmacología , Organofosfonatos , Compuestos Organofosforados/farmacología , Fosfolípidos/farmacología , Piperidinas/farmacología , Animales , Antineoplásicos/síntesis química , Proteína Quinasa CDC2/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Ciclinas/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Ratones Desnudos , Mitosis/efectos de los fármacos , Estructura Molecular , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Compuestos Organofosforados/síntesis química , Fosfolípidos/síntesis química , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Piperidinas/síntesis química , Estrellas de Mar , Células Tumorales Cultivadas , Fosfatasas cdc25RESUMEN
A series of 2-, 3-, and 4-substituted phenylalkyl amides were prepared as potential melatonin analogs in order to investigate the nature of the binding site of the melatonin receptor in chicken brain. The length of the alkyl chain was systematically varied from n = 1 to 4, and methoxyl substituents were incorporated into the phenyl ring at the 2-, 3-, and 4-positions. The maximum binding affinity was found to occur when n = 3 and when the methoxyl substituent was in the 3-position, the direct analog of the carbon framework of melatonin in which the 1,2-atoms of the indole ring have been removed. Whereas there was only a relatively small decrease in binding affinity for the corresponding 2-methoxy derivatives, 4-methoxyl substitution led to a large decrease in binding affinity, suggesting that the binding sites for the side chain and methoxyl group could not now be occupied at the same time. As in the indole analogs of melatonin, replacement of the methyl group of the amide by a longer alkyl chain led to an increase in binding affinity for ethyl and propyl with a subsequent decrease in binding affinity for butyl chains. Thus N-propanoyl-3-(3-methoxyphenyl)propanamine (6f) has a binding affinity of 5.6 nM, a remarkably high affinity for so simple a compound. Substitution of halogen for 3-methoxyl in the propanamide series gave a series of compounds with lower, but still substantial, binding affinities, the 3-chloro derivative 7e showing the highest affinity, 113 nM. In the case of the 3-fluoro propanamides, a maximum in the binding affinity was not observed in the series synthesized, and these derivatives will merit further exploration. These results demonstrate the utility of simple, readily modified phenylalkylamines as a "framework" for studying the effect of changes in the nature and position of substituents on the melatonin receptor binding affinity.
Asunto(s)
Amidas/metabolismo , Receptores de Superficie Celular/química , Animales , Pollos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas/métodos , Unión Proteica , Receptores de Superficie Celular/metabolismo , Receptores de MelatoninaRESUMEN
The preparation of phenyl-ring substituted 4-morpholino-1-phenylthio-2-butanones 4a-e is described. These compounds were evaluated against P-388 leukemia and human cancer rhinopharynx KB cells in vitro; some compounds were found to exhibit activity against these cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Butanonas/síntesis química , Animales , Antineoplásicos/farmacología , Butanonas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células KB/efectos de los fármacos , Leucemia P388/tratamiento farmacológico , Bases de Mannich/síntesis química , Bases de Mannich/farmacología , Ratones , Espectrofotometría InfrarrojaRESUMEN
New derivatives of benzofuran were prepared and evaluated for their in vitro activity against a number of DNA and RNA viruses in various cell systems. Compounds 1-(7-dodecyloxy-2-benzofuranyl)ethanone (3c) and 1-(7-tridecyloxy-2-benzofuranyl)ethanone (3d) exhibited a specific activity against respiratory syncytial virus in HeLa and compound [di(2-acetylbenzofuranyl-7-oxy)]-n-propane (5a) against influenza A virus in MDCK.