RESUMEN

We conducted a screening program for vasoactive compounds and detected a potent activity in the cultured broth of Streptomyces sp. SANK 63697. From the cultured broth, two active compounds, vestaine A1 and B1, were isolated. The structures of these compounds were elucidated by physicochemical data and spectral analyses, and found to be new compounds.

Asunto(s)

Acetilcisteína/análogos & derivados , Compuestos de Amonio Cuaternario/metabolismo , Streptomyces/metabolismo , Acetilcisteína/química , Acetilcisteína/metabolismo , Acetilcisteína/farmacología , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacología , Técnicas de Cocultivo , Células Endoteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Humanos , Estructura Molecular , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología

RESUMEN

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is a key molecule in the regulation of both angiogenesis and vascular permeability. However, it is known that overproduction of VEGF induces abnormal blood vessel formation and these vessels cause several disease pathologies, such as diabetic retinopathy. The purpose of this study was to find novel vasoactive compounds which have different properties from VEGF. METHODS/RESULTS: We screened a natural product library using a co-culture angiogenic assay of endothelial cells and fibroblasts. By focusing on morphological changes of endothelial cells, we isolated the novel compounds vestaine A1 and vestaine B1 from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 63697. Vestaine A1 enhanced tube formation of endothelial cells in Matrigel and suppressed cell death induced by serum deprivation. Vestaine A1 activated both MEK1/2 and PI-3 kinase pathways independently of the VEGF pathway in a dose- and time-dependent fashion. Finally, vestaine A1 potently suppressed VEGF-induced vascular permeability both in vitro and in vivo. CONCLUSION: Vestaine A1 has the potential to exhibit both pro-angiogenic and anti-permeability properties, and would therefore be useful for therapeutic treatment for abnormal vascular permeability-related diseases.

Asunto(s)

Acetilcisteína/análogos & derivados , Inductores de la Angiogénesis/farmacología , Productos Biológicos/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Streptomyces/química , Acetilcisteína/química , Acetilcisteína/aislamiento & purificación , Acetilcisteína/farmacología , Inductores de la Angiogénesis/química , Inductores de la Angiogénesis/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Permeabilidad Capilar/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Colágeno/química , Combinación de Medicamentos , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Laminina/química , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/genética , MAP Quinasa Quinasa 2/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Cultivo Primario de Células , Proteoglicanos/química , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/aislamiento & purificación , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/aislamiento & purificación , Streptomyces/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/farmacología

RESUMEN

Caramel color is widely used in the food industry, and its many variations are generally considered to be safe. It has been known for a long time that THI (2-acetyl-4-(tetrahydroxybutyl)imidazole), a component of caramel color III, causes lymphopenia in animals through sphingosine 1-phosphate (S1P) lyase (S1PL) inhibition. However, this mechanism of action has not been fully validated because THI does not inhibit S1PL in vitro. To reconcile this situation, we examined molecular details of THI mechanism of action using "smaller" THI derivatives. We identified a bioactive derivative, A6770, which has the same lymphopenic effect as THI via S1PL inhibition. In the case of A6770 we observe this effect both in vitro and in vivo, and demonstrate that A6770 is phosphorylated and inhibits S1PL in the same way as 4-deoxypyridoxine. In addition, A6770 was detected in rat plasma following oral administration of THI, suggesting that A6770 is a key metabolic intermediate of THI.

Asunto(s)

Colorantes de Alimentos/farmacología , Imidazoles/farmacología , Linfopenia/inducido químicamente , Linfopenia/metabolismo , Lisofosfolípidos/antagonistas & inhibidores , Esfingosina/análogos & derivados , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Colorantes de Alimentos/administración & dosificación , Colorantes de Alimentos/química , Imidazoles/administración & dosificación , Imidazoles/química , Lisofosfolípidos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas Lew , Esfingosina/antagonistas & inhibidores , Esfingosina/metabolismo , Relación Estructura-Actividad

RESUMEN

We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 µg/mL; JP2, 462 µg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.

Asunto(s)

Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Integrina alfa4beta1/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Asma/inmunología , Disponibilidad Biológica , Bronquios/efectos de los fármacos , Bronquios/inmunología , Línea Celular , Ácidos Ciclohexanocarboxílicos/administración & dosificación , Ácidos Ciclohexanocarboxílicos/farmacocinética , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Femenino , Haplorrinos , Humanos , Integrina alfa4beta1/inmunología , Ratones , Ratones Endogámicos BALB C , Pirrolidinas/administración & dosificación , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapéutico , Solubilidad , Agua/química

RESUMEN

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.

Asunto(s)

Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/síntesis química , Integrina alfa4beta1/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinas/síntesis química , Integrina alfa4beta1/metabolismo , Cetonas/química , Oxidación-Reducción , Estereoisomerismo

RESUMEN

For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N'-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3-yl)-1,3-benzoxazolyl group as a novel replacement of the (N'-phenylureido)phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse α(4) antibody (R1-2).

Asunto(s)

Asma/tratamiento farmacológico , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Integrina alfa4beta1/antagonistas & inhibidores , Administración Oral , Animales , Asma/inmunología , Bronquios/efectos de los fármacos , Bronquios/inmunología , Lavado Broncoalveolar , Línea Celular , Ácidos Ciclohexanocarboxílicos/farmacocinética , Ácidos Ciclohexanocarboxílicos/farmacología , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Relación Estructura-Actividad

RESUMEN

This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu4NSO3H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material.

Asunto(s)

Antiasmáticos/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Amidas/química , Antiasmáticos/síntesis química , Antiasmáticos/química , Ciclización , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Éteres/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Pirrolidinas/química , Espectrofotometría Infrarroja , Estereoisomerismo

RESUMEN

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

Asunto(s)

Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Indoles/farmacocinética , Integrina alfa4beta1/antagonistas & inhibidores , Pirrolidinas/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacología , Perros , Cobayas , Haplorrinos , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Ratones , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad

RESUMEN

During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC(50)=19 nM) in VLA-4 inhibitory activity compared to 1 (IC(50)=1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50)=2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL=3.3 ml/min/kg, F=51%) in rats.

Asunto(s)

Benzoxazoles/química , Ácidos Ciclohexanocarboxílicos/química , Integrina alfa4beta1/antagonistas & inhibidores , Animales , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Concentración 50 Inhibidora , Integrina alfa4beta1/metabolismo , Masculino , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad

RESUMEN

The synthesis and evaluation of new analogues of thieno[2,3-d]pyrimidin-4-yl hydrazones are described. 2-Pyrdinecarboxaldehyde [6-(tert-butyl)thieno[2,3-d]pyrimidine-4-yl]hydrazone derivatives have been identified as cyclin-dependent kinase 4 (CDK4) inhibitors. The potency, selectivity profile, and structure-activity relationship of this series of compounds are discussed.

Asunto(s)

Ciclina D1/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Hidrazonas/síntesis química , Hidrazonas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazonas/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Relación Estructura-Actividad

RESUMEN

Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.

Asunto(s)

Benzoatos/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Pirroles/farmacología , Administración Oral , Animales , Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Benzoatos/administración & dosificación , Benzoatos/síntesis química , Células Cultivadas , Modelos Animales de Enfermedad , Perros , Femenino , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Permeabilidad , Pirroles/administración & dosificación , Pirroles/síntesis química , Ratas

RESUMEN

A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL=18.5 ml/min/kg,F=28%; rats, CL=5.2 ml/min/kg,F=36%; dogs, CL=3.6 ml/min/kg,F=55%). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.

Asunto(s)

Benzoatos/síntesis química , Benzoatos/farmacocinética , Integrina alfa4beta1/antagonistas & inhibidores , Administración Oral , Animales , Benzoatos/farmacología , Modelos Animales de Enfermedad , Perros , Inflamación/tratamiento farmacológico , Concentración 50 Inhibidora , Ratones , Farmacocinética , Pleuresia/tratamiento farmacológico , Ratas , Relación Estructura-Actividad

RESUMEN

A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.

Asunto(s)

Asma/tratamiento farmacológico , Benzoatos/administración & dosificación , Benzoatos/farmacocinética , Integrina alfa4beta1/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Administración Oral , Animales , Benzoatos/química , Permeabilidad de la Membrana Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Éteres de Hidroxibenzoatos , Riñón/citología , Masculino , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Pirrolidinonas/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

The isolate from a canine disseminated protothecosis was identified to be Prototheca wickerhamii by its morphological and biochemical characteristics. The isolate was grouped into a cluster identical to the type strain of P. wickerhamii, ATCC 16529(T) in phylogenetic trees based on the small subunit (SSU) and the 5' end of the large subunit (LSU) ribosomal DNA (rDNA); the cluster was close to that including the other Prototheca species. However, the strains of P. wickerhamii, SAG 263-11 and Pore 1283 belonged to a cluster different from the other isolates of Prototheca species and closely related to those of Auxenochorella species. Therefore, P. wickerhamii could be divided into two distinct genetic groups, one group close to the other Prototheca spp. including a standard strain of P. wickerhamii, and another group consisting of isolates previously reported to be close to the Auxenochorella species.

Asunto(s)

ADN Ribosómico/genética , Enfermedades de los Perros/diagnóstico , Infecciones/veterinaria , Filogenia , Prototheca/clasificación , Prototheca/aislamiento & purificación , Animales , Análisis por Conglomerados , Perros , Resultado Fatal , Femenino , Infecciones/diagnóstico

RESUMEN

The formation reaction and the intercalation of adenosine triphosphate (ATP) were studied for hydrotalcite (HT), a layered double hydroxide (LDH) of magnesium and aluminum. Hydrotalcite with nitrate ions in the interlayer (HT-NO(3)) was formed (A) by dropwise addition of a solution of magnesium and aluminum nitrates (pH ca. 3) to a sodium hydroxide solution (pH ca. 14) until the pH decreased from 14 to 10 and (B) by dropwise addition of the NaOH solution to the solution of magnesium and aluminum nitrates with pH increasing from 3 to 10. The precipitate obtained with method B was contaminated with aluminum hydroxide and the crystallinity of the product was low, possibly because aluminum hydroxide precipitates at pH 4 or 5 and remains even after HT-NO(3) forms at pH above 8. With method A, however, the precipitate was pure HT-NO(3) with increased crystallinity, since the solubility of aluminum hydroxide at pH above and around 10 is high as dissolved aluminate anions are stable in this high pH region, and there was no aluminum hydroxide contamination. The formed HT-NO(3) had a composition of [Mg(0.71)Al(0.29)(OH)(2)](NO(3))(0.29).0.58H(2)O. To intercalate ATP anions into the HT-NO(3), HT-NO(3) was dispersed in an ATP solution at pH 7. It was found that the interlayer nitrate ions were completely exchanged with ATP anions by ion exchange, and the interlayer distance expanded almost twice with a free space distance of 1.2 nm. The composition of HT-ATP was established as [Mg(0.68)Al(0.32)(OH)(2)](ATP)(0.080)0.88H(2)O. The increased distance could be explained with a calculated molecular configuration of the ATP as follows: An ATP molecule is bound to an interlayer surface with the triphosphate group, the adenosine group bends owing to its bond angles and projects into the interlayer to a height of 1 nm, and the adenosine groups aligned in the interlayer support the interlayer distance.

Asunto(s)

Adenosina Trifosfato/química , Hidróxido de Aluminio/química , Aniones , Hidróxidos , Hidróxido de Magnesio/química , Agua/química , Adenosina/química , Cromatografía por Intercambio Iónico/métodos , Concentración de Iones de Hidrógeno , Iones , Magnesio/química , Modelos Químicos , Fosfatos/química , Temperatura , Difracción de Rayos X

RESUMEN

A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).

Asunto(s)

Acetatos/síntesis química , Integrina alfa4beta1/antagonistas & inhibidores , Piperazinas/síntesis química , Piperidinas/síntesis química , Prolina/análogos & derivados , Acetatos/farmacocinética , Acetatos/farmacología , Animales , Perros , Espectroscopía de Resonancia Magnética , Masculino , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperidinas/farmacocinética , Piperidinas/farmacología , Prolina/síntesis química , Prolina/farmacocinética , Prolina/farmacología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa Bombardeada por Átomos Veloces

RESUMEN

BACKGROUND: Panton-Valentine leukocidin (PVL) is mainly associated with necrotic suppurative lesions, such as furuncles and abscesses in the skin and subcutaneous tissue, but it has also been isolated from patients with community-acquired, severe, necrotizing pneumonia. However, the clinical manifestations of furuncles caused by PVL-producing Staphylococcus aureus and the role of patients' background are not fully understood. METHODS: We used polymerase chain reaction amplification to test for the PVL gene in 161 strains of S. aureus isolated from suppurative skin lesions. For all PVL gene-positive strains isolated from furuncles, we analyzed cutaneous manifestations, patient background characteristics, and bacteriological markers, including coagulase types, presence of the mecA gene, and toxin profiles, and we compared these results with those for PVL gene-negative strains. RESULTS: PVL genes were detected in 16 (40%) of the 40 S. aureus strains isolated from furuncles, 2 (28%) of the 7 strains isolated from carbuncles, 1 (14%) of the 7 strains isolated from abscesses, and 1 (5%) of the 20 strains isolated from folliculitis. PVL gene-positive S. aureus usually causes multiple (rather than single) furuncles, and such furuncles are usually associated with more-intense erythema around the lesions. PVL gene-positive strains were isolated from young adults without underlying diseases, whereas PVL gene-negative strains were isolated from patients with various systemic complications, including diabetes, leukemia, and autoimmune diseases. CONCLUSIONS: PVL gene-positive S. aureus strains are involved in the development of multiple furuncles with more-intense erythema, particularly in healthy young adults. An understanding of the characteristics of furuncles due to PVL gene-positive strains might be useful for preventing the development of the severe systemic infections.

Asunto(s)

Toxinas Bacterianas/genética , Exotoxinas/genética , Infecciones Cutáneas Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Adolescente , Adulto , Niño , Preescolar , Humanos , Lactante , Leucocidinas , Persona de Mediana Edad , Piel/patología , Infecciones Cutáneas Estafilocócicas/patología

RESUMEN

An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.

Asunto(s)

Integrina alfa4beta1/antagonistas & inhibidores , Morfolinas/farmacología , Piperidinas/farmacología , Administración Oral , Animales , Asma/etiología , Asma/metabolismo , Ratones , Morfolinas/administración & dosificación , Morfolinas/química , Piperidinas/administración & dosificación , Piperidinas/química

RESUMEN

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.

Asunto(s)

Taxoides/síntesis química , Acetales/síntesis química , Acetales/metabolismo , Acetales/farmacología , Animales , Antineoplásicos , División Celular/efectos de los fármacos , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Relación Estructura-Actividad , Taxoides/metabolismo , Taxoides/farmacología

RESUMEN

This paper describes a convenient synthetic procedure for nucleoside mimics, 1-6, in which the 3',5'-hydroxy groups of natural 2'-deoxythymidine or 2'-deoxyadenosine are replaced by thiol, amine, or alkylthiol groups. Such nucleosides would be built up into a single DNA strand with cooperative participation of metal coordination, where internucleoside linkages are replaced by metal complexation motifs. The X-ray crystal structure and complexation behaviors of 3',5'-dithiothymidine, 1, with Au(I) are also reported.

Asunto(s)

ADN , Nucleósidos/síntesis química , Alquenos/química , Aminas/química , Cristalografía por Rayos X , Oro , Modelos Moleculares , Imitación Molecular , Estructura Molecular , Conformación de Ácido Nucleico , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/química