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1.
J Med Chem ; 62(5): 2265-2285, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

2.
Oncol Lett ; 13(5): 3379-3386, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28521443

RESUMO

Previous studies have investigated the mechanisms of immune evasion of tumor cells in numerous types of advanced solid malignant tumor, and several types of immune preparations have been administered as antitumor adjuvant therapies. However, in the majority of studies, the efficacy of therapies has been revealed to be limited. The present study aimed to investigate the immune evasion mechanisms employed by early colorectal cancer cells and the expression of the molecules associated with immune evasion during the malignant transformation process of normal colorectal epithelial cells to measure the effects of immune intervention for early colorectal cancer, and to improve the efficacy of immunotherapy. A total of 60 colorectal tissues, including 15 normal mucosa, 15 adenoma, 15 early cancer and 15 advanced cancer tissues, from patients undergoing endoscopic procedures in Huadong Hospital Affiliated to Fudan University (Shanghai, China) were collected. A comparison of baseline characteristics among these four groups was performed. The expression levels of human leukocyte antigen-A (HLA-A), apoptosis antigen 1 (Fas), c-c chemokine receptor type 5 (CCR5), Fas ligand (FasL) and HLA-E in each group were detected by immunohistochemical analysis. Furthermore, 15 patients with advanced colorectal cancer were enrolled into the present study. Advanced cancer and paracancer tissues (normal mucosal tissues 3 cm away from the margin of cancer tissues) were collected from each patient by colonoscopic biopsy. The expression levels of HLA-A, Fas, CCR5, FasL and HLA-E in each group were detected by western blot analysis. During the malignant transformation process of normal colorectal epithelial cells, the expression levels of CCR5, FasL and HLA-E increased significantly (P<0.001), whilst the expression levels of Fas reduced significantly (P=0.0271). In the early cancer group, the expression levels of Fas reduced significantly (P=0.0239), whilst the expression levels of HLA-E increased significantly (P<0.001) compared with adenoma group. In conclusion, a loss of Fas expression and high expression levels of HLA-E may promote the immune evasion of early colorectal cancer cells.

3.
J Med Chem ; 59(24): 11138-11147, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28002964

RESUMO

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Naftalenos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
4.
Mol Med Rep ; 14(2): 1162-72, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27279428

RESUMO

Diabetic nephropathy (DN), a common diabetes-related complication, is the leading cause of progressive chronic kidney disease (CKD) and end­stage renal disease. Despite the rapid development in the treatment of DN, currently available therapies used in early DN cannot prevent progressive CKD. The exact pathogenic mechanisms and the molecular events underlying DN development remain unclear. Ginsenoside Rg3 is a herbal medicine with numerous pharmacological effects. To gain a greater understanding of the molecular mechanism and signaling pathway underlying the effect of ginsenoside Rg3 in DN therapy, an RNA sequencing approach was performed to screen differential gene expression in a rat model of DN treated with ginsenoside Rg3. A combined bioinformatics analysis was then conducted to obtain insights into the underlying molecular mechanisms of the disease development, in order to identify potential novel targets for the treatment of DN. Six Sprague­Dawley male rats were randomly divided into 3 groups: Normal control group, DN group and ginsenoside­Rg3 treatment group, with two rats in each group. RNA sequencing was adopted for transcriptome profiling of cells from the renal cortex of DN rat model. Differentially expressed genes were screened out. Cluster analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to analyze the differentially expressed genes. In total, 78 differentially expressed genes in the DN control group were identified when compared with the normal control group, of which 52 genes were upregulated and 26 genes were downregulated. Differential expression of 43 genes was observed in the ginsenoside­Rg3 treatment group when compared with the DN control group, consisting of 10 upregulated genes and 33 downregulated genes. Notably, 21 that were downregulated in the DN control group compared with the control were then shown to be upregulated in the ginsenoside­Rg3 treatment group compared with the DN control group. In addition, 7 upregulated genes in the DN control group compared with the control were then shown to be downregulated in the ginsenoside­Rg3 treatment group compared with the DN control group. Cluster analysis based on differentially expressed genes indicated that the transcriptomes are quite different among the samples. Distinct GO terms associated with these groups of genes were shown to be enriched. KEGG pathway analysis demonstrated that differentially expressed genes were predominantly involved in the fatty acid metabolism pathway and peroxisome proliferator­activated receptor (PPAR) signaling pathway. To the best of our knowledge, this study was the first to present whole genome expression profiling in DN with ginsenoside­Rg3 treatment by RNA­Seq. A set of differentially expressed genes and pathways were identified. These data provided an insight into understanding the molecular mechanisms underlying the effect of ginsenoside­Rg3 treatment of DN.


Assuntos
Biologia Computacional , Nefropatias Diabéticas/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Genômica , Ginsenosídeos/farmacologia , Transcriptoma , Animais , Estudos de Casos e Controles , Análise por Conglomerados , Biologia Computacional/métodos , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Ontologia Genética , Redes Reguladoras de Genes , Genômica/métodos , Masculino , Anotação de Sequência Molecular , Ratos , Transdução de Sinais
5.
Water Sci Technol ; 72(5): 754-61, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26287834

RESUMO

The wastewater of silicon photovoltaic (PV) battery manufacturing contained polyethylene glycol (PEG) and detergents, which possessed the characteristics of high content of organics and low bioavailability, and then resulted in high treatment costs. To address the difficulties of existing treatment facilities in stably meeting discharge standards, eight tons of microbial culture (consisting of Bacillus sp. and Rhodococcus sp.) were added into the aerobic treatment unit. Subsequently, the effectiveness of the microbial culture in small-scale biological wastewater treatment was evaluated, and the operating conditions for engineering applications were optimized. The application study showed that the average chemical oxygen demand (COD) removal efficiency reached 95.0% when the pH value was 7, the gas-water ratio was 28:1, the reflux ratio was 50%, which indicated an increase of 51.2% contrasting with the situation without bioaugmentation. The volume load of the treatment facilities after augmentation increased by 127.9% and could tolerate the COD shock load reached 2,340 mg·L(-1). At last, the effluence met the class I standard of the Integrated Wastewater Discharge Standard (GB8978-1996).


Assuntos
Bacillus/metabolismo , Detergentes/metabolismo , Polietilenoglicóis/metabolismo , Rhodococcus/metabolismo , Poluentes Químicos da Água/metabolismo , Análise da Demanda Biológica de Oxigênio , Resíduos Industriais , Águas Residuárias , Purificação da Água
6.
J Med Chem ; 58(10): 4278-90, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25905990

RESUMO

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/metabolismo , Tiadiazóis/farmacologia , Animais , Sangue/efeitos dos fármacos , Sangue/metabolismo , Técnicas de Química Sintética , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Ratos Endogâmicos Lew , Receptores de Glucocorticoides/agonistas , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacocinética , Fator de Transcrição AP-1/metabolismo
7.
Bioorg Med Chem Lett ; 24(15): 3268-73, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24980053

RESUMO

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.


Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/agonistas , Tiadiazóis/farmacologia , Ureia/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Ureia/análogos & derivados , Ureia/química
8.
Bioorg Med Chem Lett ; 24(7): 1843-5, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24613378

RESUMO

We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.


Assuntos
Receptores CCR2/antagonistas & inibidores , Sulfonas/química , Animais , Cicloexanos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Conformação Molecular , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 23(24): 6902-4, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24169233

RESUMO

Anti-microtubule agents such as paclitaxel and docetaxel have played an important role in the treatment of cancer for many years. Recently, a small molecule that has a taxol-like mode of action (5HPP-33) was reported. Herein, the detailed structure-activity relationship (SAR) studies of 5HPP-33 analogs that are substituted at the isoindole and phenyl rings are described. Bulky substitutions (such as di-isopropyl groups) on the phenyl ring result in the isoindole and phenyl rings being perpendicular to each other. It was found that this conformation is critical for anti-microtubule activity. These studies have provided valuable information, which will be helpful in the design of more potent analogs.


Assuntos
Isoindóis/química , Microtúbulos/química , Paclitaxel/química , Talidomida/análogos & derivados , Talidomida/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoindóis/síntese química , Isoindóis/farmacologia , Microtúbulos/metabolismo , Relação Estrutura-Atividade , Talidomida/síntese química , Moduladores de Tubulina/síntese química
10.
Bioorg Med Chem Lett ; 22(3): 1384-7, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22225639

RESUMO

We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.


Assuntos
Amidas/síntese química , Aminobenzoatos/síntese química , Modelos Moleculares , Receptores CCR2/antagonistas & inibidores , Enxofre/química , Amidas/química , Amidas/farmacologia , Aminobenzoatos/química , Aminobenzoatos/farmacologia , Animais , Ciclização , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/enzimologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Enxofre/farmacologia
11.
J Med Chem ; 53(9): 3814-30, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405922

RESUMO

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.


Assuntos
Hidantoínas/farmacocinética , Fatores Imunológicos/química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Ácidos Nicotínicos/farmacocinética , Humanos , Hidantoínas/farmacologia , Antígeno-1 Associado à Função Linfocitária/química , Antígeno-1 Associado à Função Linfocitária/imunologia , Ácidos Nicotínicos/toxicidade , Relação Estrutura-Atividade
12.
Org Lett ; 11(6): 1421-4, 2009 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-19243133

RESUMO

A novel synthesis of 3-substituted 4(3H)-quinazolinones via HATU-mediated coupling of 4-hydroxyquinazolines with primary amines has been developed. Under mild reaction conditions, the products were achieved in good yield from commercially available starting materials.


Assuntos
Aminas/química , Técnicas de Química Combinatória , Quinazolinonas/síntese química , Estrutura Molecular , Quinazolinonas/química
13.
J Med Chem ; 50(15): 3730-42, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17585753

RESUMO

Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.


Assuntos
Acridinas/síntese química , IMP Desidrogenase/antagonistas & inibidores , Piperazinas/síntese química , Acridinas/farmacologia , Acridinas/toxicidade , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Linhagem Celular , Proliferação de Células , Trato Gastrointestinal/efeitos dos fármacos , Meia-Vida , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Macaca fascicularis , Masculino , Piperazinas/farmacologia , Piperazinas/toxicidade , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Relação Estrutura-Atividade
14.
Anticancer Res ; 27(6B): 3801-6, 2007 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18225535

RESUMO

BACKGROUND: The mammary glands of adult female animals are remarkably sensitive to keratinocyte growth factor (KGF). KGF acts at the KGF receptor (KGFR) to produce a rapid and profound stimulation of breast cancer cell proliferation and motility. Further, KGF-induced motility in breast cancer cells is mediated via the Erk1/2 signaling pathway. Thus, enhancement of KGF/KGFR signal transduction may be an early step in the metastatic progression of breast cancer. Receptor modeling of KGFR was used to identify selective KGFR tyrosine kinase inhibitor (TKI) molecules with high receptor affinity. The present study describes the synthesis and biological activity of three of the KGFR TKI compounds. MATERIALS AND METHODS: Computer modeling of the KGFR was used to create a virtual library of compounds that have the potential to bind with high affinity to the KGFR. Three of these compounds were synthesized and tested in this study. The compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation and motility using a culture wounding assay. In addition, the effect of the most potent KGFR TKI compound on the relative density of cell membrane KGFR was measured using immunocytochemistry. RESULTS: It was observed that the KGFR TKIs decreased KGF-mediated activity as predicted by computer modeling. In addition, the most potent inhibitor also reduced the density of the KGFR on the membrane of the cancer cells. CONCLUSION: The novel inhibitors identified in this project are selective KGFR inhibitors which appear to reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the chemoprevention of metastatic cancer development and provide a new approach in the treatment of breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desenho de Drogas , Humanos , Imuno-Histoquímica , Quinolonas/síntese química , Quinolonas/farmacologia
15.
J Med Chem ; 49(24): 6946-9, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125246

RESUMO

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.


Assuntos
Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/síntese química , Tiofenos/síntese química , Animais , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Rejeição de Enxerto/prevenção & controle , Humanos , Antígeno-1 Associado à Função Linfocitária/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Transplante Homólogo
16.
Bioorg Med Chem Lett ; 15(24): 5382-5, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16213720

RESUMO

A series of compounds originally derived from the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, was synthesized and evaluated. The most potent compound in this series, compound 7, structurally resembles the potent anti-microtubule agent Combretastatin A-4, inhibited tubulin polymerization, and showed potent growth inhibitory activities on both prostate and breast cancer lines with IC(50) values in low to subnanomolar range.


Assuntos
Indóis/química , Pirróis/química , Estilbenos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Divisão Celular/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Suínos , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
17.
Bioorg Med Chem Lett ; 13(6): 1187-9, 2003 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-12643940

RESUMO

The synthesis and anti-angiogenic activities of linomide and its analogues are reported. Three of the analogues are 3.3-69 times more potent than linomide at inhibiting blood vessel formation in the CAM angiogenesis assay. These compounds possessed considerable anti-proliferative activity against isolated HUVEC cells with no activity against epithelial-derived prostate tumor cells.


Assuntos
Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Alantoína/química , Animais , Divisão Celular/efeitos dos fármacos , Embrião de Galinha , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Masculino , Membranas/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Steroids ; 67(10): 821-6, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12231117

RESUMO

The enzyme steryl sulfatase may help support the growth of hormone-dependent tumors, including prostate cancers, by facilitating the conversion of circulating precursor steroids to active hormones. We sought to determine the presence of steryl sulfatase activity in the androgen-dependent human prostate cancer cell line LNCaP, and to determine if this activity was inhibited by known steryl sulfatase inhibitors. Intact LNCaP cultures had steryl sulfatase activity, as determined by conversion of [3H]estrone sulfate (E(1)S) to unconjugated steroids. The level of steryl sulfatase activity was relatively low (4.6 pmol/18 h/million cells) compared to MDA-MB-231 breast cancer cells (284.0 pmol/18 h/million cells). The observed activity in both cell lines was blocked by addition of 1 microM estrone sulfamate (EMATE), an active-site-directed, steroidal inhibitor of steryl sulfatase. Steryl sulfatase activity was also inhibited by Danazol, and by (p-O-sulfamoyl)-tetradecanoyl tyramine (C2-14), a non-steroidal inhibitor. Microsomes prepared from LNCaP cultures also showed steryl sulfatase activity, as determined by hydrolysis of [3H]E(1)S and [3H]dehydroepiandrosterone sulfate (DHEAS) to unconjugated forms. LNCaP and MDA-MB-231 microsomes both hydrolyzed E(1)S about two times faster than DHEAS. Hydrolysis of E(1)S in LNCaP and MDA-MB-231 microsomes was blocked by steryl sulfatase inhibitors with the following relative potencies: EMATE>C2-14>Danazol. These data demonstrate that LNCaP prostate cancer cells contain a steryl sulfatase with properties similar to that found in human breast cancer cells, and that the activity of this enzyme can be blocked by known steryl sulfatase inhibitors. Steryl sulfatase inhibitors may be useful as an adjuvant to androgen deprivation therapy for prostate cancer.


Assuntos
Arilsulfatases/antagonistas & inibidores , Estrona/análogos & derivados , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Tiramina/análogos & derivados , Arilsulfatases/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Danazol/farmacologia , Sulfato de Desidroepiandrosterona/metabolismo , Inibidores Enzimáticos/farmacologia , Estrona/metabolismo , Estrona/farmacologia , Feminino , Humanos , Cinética , Masculino , Microssomos/metabolismo , Esteril-Sulfatase , Sulfonamidas/farmacologia , Células Tumorais Cultivadas , Tiramina/farmacologia
19.
Biol Pharm Bull ; 25(5): 597-604, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12033499

RESUMO

Angiogenesis, in particular anti-angiogenesis, is an area of particular therapeutic interest in cancer treatment. Several anti-angiogenic agents are in the final stages of clinical trials. One of these agents, thalidomide, best known for its teratogenic potential, is showing promise against several tumor types. Thalidomide has been shown previously to require bio-activation to exert its anti-angiogenic effect in isolated blood vessels and endothelial cells. In this work, we confirmed these findings using the in utero chicken embryo chorioallantoic membrane (CAM) system. In particular, the anti-angiogenic effect of thalidomide is significantly enhanced by activation by human but not by rat liver microsomes. We also showed in the CAM assay that hydroxylation of thalidomide at either the 1'- or 5-position retained anti-angiogenic activity whereas its hydroxylation at the 4-position led to an inactive compound. We further demonstrated that thalidomide shows weak anti-proliferative activity against MDA-MB-231 human breast cancer cells in culture. Thalidomide showed slightly more anti-proliferative activity, however, against the SH-SY5Y human neuroblastoma and human umbilical vein endothelial cell (HUVEC) types. Furthermore, incubation of thalidomide with human liver microsomes added no additional anti-proliferative effect in these cell types versus thalidomide given alone. Finally, we report that none of the thalidomide metabolites tested had any anti-proliferative effect against the breast or neuroblastoma cells, but do possess appreciable anti-proliferative activity against the endothelial cells. In summary, this work suggests that hydroxylated thalidomide analogs based on putative metabolites of the drug possess significant anti-angiogenic activity and that exploring further derivatives of these as potential anti-angiogenic agents warrants further merit.


Assuntos
Inibidores da Angiogênese , Vasos Sanguíneos/efeitos dos fármacos , Córion/irrigação sanguínea , Endotélio Vascular/citologia , Talidomida/farmacologia , Animais , Antimetabólitos/farmacologia , Bromodesoxiuridina/farmacologia , Divisão Celular/efeitos dos fármacos , Embrião de Galinha , Endotélio Vascular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Hidroxilação , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Ratos , Fluxo Sanguíneo Regional , Talidomida/metabolismo , Células Tumorais Cultivadas
20.
J Comb Chem ; 4(2): 149-53, 2002 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11886289

RESUMO

A novel solid-phase synthesis of thalidomide and its metabolites and analogues is described. The synthetic strategy involves the coupling of hydroxymethyl polystyrene with phthalic anhydride to form the resin-linked acid. The acid is then reacted with primary amines followed by acid or base treatment to form thalidomide and its analogues with either open or closed phthalimide rings. Most of the analogues are synthesized with high yields (40.3-98.1% in three steps) and purities (92.3-98.9%).


Assuntos
Inibidores da Angiogênese/síntese química , Talidomida/análogos & derivados , Talidomida/síntese química , Técnicas de Química Combinatória , Humanos , Talidomida/farmacologia
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