Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Chemistry ; 23(33): 7910-7914, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28449309

RESUMO

Herein we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin αV ß3 . Conjugate 2 was synthesized by connecting the isoDGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val-Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin αV ß3 receptor (IC50 =11.0 nm). The tumor targeting ability of conjugate 2 was assessed in vitro in anti-proliferative assays on two isogenic cancer cell lines characterized by different integrin αV ß3 expression: human glioblastoma U87 (αV ß3 +) and U87 ß3 -KO (αV ß3 -). The isoDGR-PTX conjugate 2 displayed a remarkable targeting index (TI=9.9), especially when compared to the strictly related RGD-PTX conjugate 4 (TI=2.4).


Assuntos
Oligopeptídeos/química , Paclitaxel/química , Sequência de Aminoácidos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Peptidomiméticos/química , Peptidomiméticos/toxicidade
2.
Chemistry ; 21(18): 6921-9, 2015 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-25784522

RESUMO

Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvß3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVß3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVß3-) and its subclone CCRF-CEM αVß3 (αVß3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVß3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.


Assuntos
Antineoplásicos/síntese química , Dicetopiperazinas/química , Lisossomos/química , Oligopeptídeos/química , Paclitaxel/análogos & derivados , Peptídeos Cíclicos/síntese química , Peptidomiméticos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Integrina alfaVbeta3/metabolismo , Ligantes , Estrutura Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/farmacologia
3.
Bioorg Med Chem ; 21(23): 7364-80, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24139169

RESUMO

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazinas/química , Pirazinas/farmacologia , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-pim-1/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirazinas/síntese química
4.
Bioorg Med Chem ; 18(19): 7113-20, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20817473

RESUMO

A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Tiofenos/farmacologia , Animais , Antineoplásicos/química , Aurora Quinases , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Células HL-60 , Humanos , Masculino , Camundongos , Camundongos SCID , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Pirazóis/síntese química , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Transplante Heterólogo
5.
Mol Cancer Ther ; 6(12 Pt 1): 3158-68, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18089710

RESUMO

PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.


Assuntos
Benzamidas/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Animais , Aurora Quinase B , Aurora Quinases , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Neoplasias/enzimologia , Fosforilação , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley
6.
J Med Chem ; 49(24): 7247-51, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125279

RESUMO

The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.


Assuntos
Antineoplásicos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Pirróis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Masculino , Camundongos , Modelos Moleculares , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Solubilidade , Relação Estrutura-Atividade
7.
J Med Chem ; 48(8): 2944-56, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15828833

RESUMO

Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.


Assuntos
Antineoplásicos/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Ciclina A/antagonistas & inibidores , Pirazóis/síntese química , Pirrolidinonas/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Modelos Moleculares , Permeabilidade , Fosforilação , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Ratos , Proteína do Retinoblastoma/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo
8.
J Med Chem ; 48(8): 3080-4, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15828847

RESUMO

Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.


Assuntos
Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Piperazinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirróis/síntese química , Trifosfato de Adenosina/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade
9.
J Med Chem ; 47(13): 3367-80, 2004 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-15189033

RESUMO

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.


Assuntos
Acetamidas/síntese química , Antineoplásicos/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Ciclina A/antagonistas & inibidores , Pirazóis/síntese química , Acetamidas/química , Acetamidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Quinases relacionadas a CDC2 e CDC28/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclina A/química , Quinase 2 Dependente de Ciclina , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Transplante de Neoplasias , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Transplante Heterólogo
10.
Cancer Chemother Pharmacol ; 52(6): 507-13, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12923660

RESUMO

PURPOSE: The effect of an anticancer treatment on tumor cell proliferation in vitro can be described as a three-dimensional surface where the inhibitory effect is related to drug concentration and treatment time. The analysis of this kind of response surface could provide critical information: for example, it could indicate whether a prolonged exposure to a low concentration of an anticancer agent will produce a different effect from exposure to higher concentrations for a shorter period of time. The parametric approach available in the literature was not flexible enough to accommodate the behavior of the response surface in some of the data sets collected as part of our research programs. Therefore, a new, general, nonparametric approach was developed. METHODS: The response surface of the inhibition of cell-based tumor growth was described using a radial basis function neural network (RBF-NN). The RBF-NN was trained using regularization theory, which provided the initialization of a constrained quadratic optimization algorithm that imposes monotonicity of the surface with respect to both concentration and exposure time. RESULTS: In the two analyzed cases (doxorubicin and flavopiridol), the proposed method was accurate and reliable in describing the inhibition surface of tumor cell growth as a function of drug concentration and exposure time. Residuals were small and unbiased. The new method improved on the parametric approach when the relative importance of drug concentration and exposure time in determining the overall effect was not constant across the experimental data. CONCLUSIONS: The proposed RBF-NN can be reliably applied for the analysis in cell-based tumor growth inhibition studies. This approach can be used for optimizing the administration regimens to be adopted in vivo. The use of this methodology can be easily extended to any cell-based experiment, in which the outcome can be seen as a function of two experimental variables.


Assuntos
Antineoplásicos/farmacologia , Redes Neurais de Computação , Antineoplásicos/administração & dosagem , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Humanos , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Fatores de Tempo
11.
Bioorg Med Chem Lett ; 15(5): 1315-9, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15713378

RESUMO

The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.


Assuntos
Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Pirazóis/classificação , Pirazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalização , Cristalografia por Raios X , Ciclina A/antagonistas & inibidores , Quinase 2 Dependente de Ciclina , Inibidores Enzimáticos/síntese química , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA