Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 28(8): 1397-1403, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29545102

RESUMO

Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.


Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Cães , Células HCT116 , Haplorrinos , Histonas/metabolismo , Humanos , Imidazóis/administração & dosagem , Imidazóis/síntese química , Imidazóis/farmacocinética , Camundongos , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Estereoisomerismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem Lett ; 27(23): 5349-5352, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29056248

RESUMO

(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-ß-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/farmacologia , Uridina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Conformação Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Relação Estrutura-Atividade , Uridina/análogos & derivados , Uridina/química
3.
Cancer Chemother Pharmacol ; 68(4): 923-33, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21298383

RESUMO

PURPOSE: Aurora kinases are required for orderly progression of cells through mitosis, and inhibition of these kinases by siRNA or small molecule inhibitors results in cell death. We previously reported the synthesis of SCH 1473759, a novel sub-nanomolar Aurora A/B inhibitor. METHODS: We utilized SCH 1473759 and a panel of tumor cell lines and xenograft models to gain knowledge about optimal dosing schedule and chemotherapeutic combinations for Aurora A/B inhibitors. RESULTS: SCH 1473759 was active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. Asynchronous cells required 24-h exposure to SCH 1473759 for maximal induction of >4 N DNA content and inhibition of cell growth. However, following taxane- or KSP inhibitor-induced mitotic arrest, less than 4-h exposure induced >4 N DNA content. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane- and KSP inhibitor-induced arrest. We tested various dosing schedules in vivo and demonstrated SCH 1473759 dose- and schedule-dependent anti-tumor activity in four human tumor xenograft models. Further, the efficacy was enhanced in combination with taxanes and found to be most efficacious when SCH 1473759 was dosed 12-h post-taxane treatment. CONCLUSIONS: SCH 1473759 demonstrated potent mechanism-based activity, and activity was shown to be enhanced in combination with taxanes and KSP inhibitors. This information may be useful for optimizing the clinical efficacy of Aurora inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Imidazóis/farmacologia , Cinesina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aurora Quinase A , Aurora Quinases , Linhagem Celular Tumoral , Esquema de Medicação , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Neoplasias/patologia , Pirazinas/administração & dosagem , Taxoides/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Chem ; 54(1): 201-10, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21128646

RESUMO

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.


Assuntos
Antineoplásicos/síntese química , Flúor , Imidazóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aurora Quinases , Disponibilidade Biológica , Linhagem Celular Tumoral , Deutério , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Histonas/metabolismo , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Macaca fascicularis , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Transplante Heterólogo
6.
ACS Med Chem Lett ; 1(5): 214-8, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900197

RESUMO

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 µM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

7.
J Nat Prod ; 66(5): 716-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12762817

RESUMO

Two-dimensional NMR analyses including HMBC, NOESY, and ROESY as well as 1D NOE experiments led to a reassignment of the structure of the recently identified Trichoderma hamatum metabolite TAEMC161 (1) as the previously known viridiol (2). In addition, GIAO-calculated (13)C NMR chemical shifts of 1 and 2 provided strong support for the revised structure.


Assuntos
Androstenodióis/química , Micotoxinas/química , Trichoderma/química , Isótopos de Carbono , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
8.
J Org Chem ; 67(15): 5156-63, 2002 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-12126400

RESUMO

We have successfully effected a transfer of chirality from a chiral nonracemic allene to an alpha-alkylidene and an alpha-silylidene cyclopentenone. The molybdenum-mediated examples possessing a silyl group on the terminus of the allene show good facial selectivities, but isomerization of the (E)-silylidene cyclopentenone to the (Z)-silylidene cyclopentenone occurs upon purification of these products. Alternatively, an alkyl group on the terminus of the allene undergoes cycloaddition with moderate selectivities but gives products that undergo an isomerization of the (Z)-alkylidene cyclopentenone to the (E)-alkylidene cyclopentenone when exposed to acidic conditions. Thus, erosion of the enantiomeric excesses is observed for one of the two products as a result of this isomerization. The allenic Pauson-Khand-type cycloaddition has also been effected by first isolation the (eta(6)-arene)molybdenum tricarbonyl complex, demonstrating for the first time that this is most likely the active complex in the molybdenum-mediated reactions. Attempts to increase the facial selectivity by increasing the size of the arene moiety resulted in a marginal increase in the selectivity at the expense of the yield. Based upon these results, we have concluded that altering the approach for the preparation of nonracemic alpha-alkylidene cyclopentenones is necessary in order to obtain synthetically useful levels of stereocontrol.


Assuntos
Alcadienos/síntese química , Química Orgânica/métodos , Ciclopentanos/síntese química , Silanos/síntese química , Alcadienos/química , Catálise , Ciclização , Ciclopentanos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Molibdênio/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Silanos/química , Estereoisomerismo
9.
Org Lett ; 4(11): 1931-4, 2002 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-12027650

RESUMO

[reaction: see text] Treatment of alkynyl allenes with [Rh(CO)(2)Cl](2) results in a formal [2 + 2 + 1] cycloaddition reaction. This reaction occurs with complete regioselectivity for a variety of substrates affording only 4-alkylidene cyclopentenones in good yields. Moreover, seven-membered rings have been prepared in high yields.


Assuntos
Alcadienos/química , Cristalografia por Raios X , Ciclização , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Silicones/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA