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1.
Molecules ; 26(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562106

RESUMO

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Técnicas de Química Sintética , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo
2.
J Biol Chem ; 293(32): 12415-12428, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29925593

RESUMO

Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3m on PLS neutrophils, whereas the total amount of PR3m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34+ hematopoietic stem cell model. Human CD34+ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.


Assuntos
Catepsina C/antagonistas & inibidores , Membrana Celular/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Granulomatose com Poliangiite/patologia , Mieloblastina/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/genética , Granulomatose com Poliangiite/metabolismo , Humanos , Masculino , Mieloblastina/genética , Neutrófilos/enzimologia , Proteólise , Adulto Jovem
3.
J Org Chem ; 80(6): 3264-9, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25689109

RESUMO

7-Azaindoles are versatile building blocks, especially in medicinal chemistry, where they serve as bioisosteres of indoles or purines. Herein, we present a novel rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to 3-benzylidene-1H-pyrrolo[2,3-b]pyridin-2(3H)-ones, as these substrates are exocyclic methylene lactamyl Michael acceptors. Ten new original derivatives of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one have been obtained.

4.
Cancers (Basel) ; 16(2)2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38275901

RESUMO

Extensive research is underway to develop new therapeutic strategies to counteract therapy resistance in cancers. This review presents various strategies to achieve this objective. First, we discuss different vectorization platforms capable of releasing drugs in cancer cells. Second, we delve into multitarget therapies using drug combinations and dual anticancer agents. This section will describe examples of multitarget therapies that have been used to treat solid tumors.

5.
Antibodies (Basel) ; 11(3)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-35997348

RESUMO

Bispecific antibodies (BsAbs) represent an important advance in innovative therapeutic strategies. Among the countless formats of BsAbs, fusion with molecules such as anticalins linked to a monoclonal antibody (mAb), represents an easy and low-cost way to obtain innovative molecules. We fused an anticalin against human fibronectin to a molecule biosimilar to trastuzumab (H0) or rituximab (R0), in four different positions, two on the N terminal region of heavy or light chains and two on the C terminal region. The eight BsAbs (H family (HF) 1 to 4 and R family (RF) 1 to 4) were produced and their affinity parameters and functional properties evaluated. The presence of anticalin did not change the glycosylation of the BsAb, shape or yield. The antigenic recognition of each BsAb family, Her2 for HF1 to 4 and CD20 for RF1 to 4, was slightly decreased (HF) or absent (RF) for the anticalin N-terminal in the light chain position. The anticalin recognition of FN was slightly decreased for the HF family, but a dramatic decrease was observed for RF members with lowest affinity for RF1. Moreover, functional properties of Abs, such as CD16 activation of NK, CD32-dependent phagocytosis and FcRn transcytosis, confirmed that this anticalin position leads to less efficient BsAbs, more so for RF than HF molecules. Nevertheless, all BsAbs demonstrated affinities for CD16, CD32 and FcRn, which suggests that more than affinity for FcRs is needed for a functioning antibody. Our strategy using anticalin and Abs allows for rapid generation of BsAbs, but as suggested by our results, some positions of anticalins on Abs result in less functionality.

6.
Bioorg Med Chem Lett ; 21(3): 1019-22, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21215621

RESUMO

Several thalidomide analogues were synthesized and compared to thalidomide and its more active analogue, lenalidomide, for their ability to inhibit the production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α and interleukin (IL)-6 by LPS-activated peripheral blood mononuclear cells (PBMCs). Among these compounds, two analogues containing sulfonyl group displayed interesting downregulation of TNF-α and IL-6 production.


Assuntos
Interleucina-6/metabolismo , Talidomida/análogos & derivados , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Baixo , Desenho de Fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Talidomida/síntese química , Talidomida/farmacologia
8.
Insect Biochem Mol Biol ; 124: 103403, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574597

RESUMO

Ommochromes are widespread pigments that mediate multiple functions in invertebrates. The two main families of ommochromes are ommatins and ommins, which both originate from the kynurenine pathway but differ in their backbone, thereby in their coloration and function. Despite its broad significance, how the structural diversity of ommochromes arises in vivo has remained an open question since their first description. In this study, we combined organic synthesis, analytical chemistry and organelle purification to address this issue. From a set of synthesized ommatins, we derived a fragmentation pattern that helped elucidating the structure of new ommochromes. We identified uncyclized xanthommatin as the elusive biological intermediate that links the kynurenine pathway to the ommatin pathway within ommochromasomes, the ommochrome-producing organelles. Due to its unique structure, we propose that uncyclized xanthommatin functions as a key branching metabolite in the biosynthesis and structural diversification of ommatins and ommins, from insects to cephalopods.


Assuntos
Invertebrados/metabolismo , Oxazinas , Fenotiazinas , Pigmentação , Xantenos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Dípteros/metabolismo , Olho/metabolismo , Insetos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Oxazinas/química , Oxazinas/isolamento & purificação , Oxazinas/metabolismo , Fenotiazinas/química , Fenotiazinas/isolamento & purificação , Fenotiazinas/metabolismo , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação , Pigmentos Biológicos/metabolismo , Xantenos/química , Xantenos/isolamento & purificação , Xantenos/metabolismo
9.
Biochem Pharmacol ; 131: 52-67, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28193451

RESUMO

Cathepsin C (CatC) is a tetrameric cysteine dipeptidyl aminopeptidase that plays a key role in activation of pro-inflammatory serine protease zymogens by removal of a N-terminal pro-dipeptide sequence. Loss of function mutations in the CatC gene is associated with lack of immune cell serine protease activities and cause Papillon-Lefèvre syndrome (PLS). Also, only very low levels of elastase-like protease zymogens are detected by proteome analysis of neutrophils from PLS patients. Thus, CatC inhibitors represent new alternatives for the treatment of neutrophil protease-driven inflammatory or autoimmune diseases. We aimed to experimentally inactivate and lower neutrophil elastase-like proteases by pharmacological blocking of CatC-dependent maturation in cell-based assays and in vivo. Isolated, immature bone marrow cells from healthy donors pulse-chased in the presence of a new cell permeable cyclopropyl nitrile CatC inhibitor almost totally lack elastase. We confirmed the elimination of neutrophil elastase-like proteases by prolonged inhibition of CatC in a non-human primate. We also showed that neutrophils lacking elastase-like protease activities were still recruited to inflammatory sites. These preclinical results demonstrate that the disappearance of neutrophil elastase-like proteases as observed in PLS patients can be achieved by pharmacological inhibition of bone marrow CatC. Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans.


Assuntos
Catepsina C/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Neutrófilos/enzimologia , Serina Proteases/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Estudos de Casos e Controles , Feminino , Humanos , Elastase de Leucócito/sangue , Macaca fascicularis , Doença de Papillon-Lefevre/enzimologia
10.
Biochem Pharmacol ; 83(6): 788-96, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22209715

RESUMO

The biological functions of human neutrophil proteinase 3 (PR3) remain unclear because of its close structural resemblance to neutrophil elastase and its apparent functional redundancy with the latter. Thus, all natural inhibitors of PR3 preferentially target neutrophil elastase. We have designed a selective PR3 inhibitor based on the sequence of one of its specific, sensitive FRET substrates. This azapeptide, azapro-3, inhibits free PR3 in solution, PR3 bound to neutrophil membranes, and the PR3 found in crude lung secretions from patients with chronic inflammatory pulmonary diseases. But it does not inhibit significantly neutrophil elastase or cathepsin G. Unlike most of azapeptides, this inhibitor does not form a stable acyl-enzyme complex; it is a reversible competitive inhibitor with a K(i) comparable to the K(m) of the parent substrate. Low concentrations (60 µM) of azapro-3 totally inhibited the PR3 secreted by triggered human neutrophils (200,000 cells/100 µL) and the PR3 in neutrophil homogenates and in lung secretions of patients with lung inflammation for hours. Azapro-3 also resisted proteolysis by all proteases contained in these samples for at least 2h.


Assuntos
Mieloblastina/antagonistas & inibidores , Mieloblastina/metabolismo , Neutrófilos/enzimologia , Oligopeptídeos/farmacologia , Pneumonia/enzimologia , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Sequência de Aminoácidos , Catepsina G/metabolismo , Cromatografia Líquida de Alta Pressão , Desenho de Fármacos , Citometria de Fluxo , Transferência Ressonante de Energia de Fluorescência , Humanos , Cinética , Elastase de Leucócito/antagonistas & inibidores , Elastase de Leucócito/metabolismo , Dados de Sequência Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Pneumonia/tratamento farmacológico , Ligação Proteica , Proteínas Secretadas Inibidoras de Proteinases/síntese química , Proteínas Secretadas Inibidoras de Proteinases/química , Proteólise , Escarro/enzimologia , Especificidade por Substrato , Fatores de Tempo
11.
J Pharm Biomed Anal ; 54(2): 411-6, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-20869830

RESUMO

A new method based on high-performance liquid chromatography coupled to ultraviolet and evaporative light scattering detection (HPLC-UV-ELSD) was developed for the determination of L-glutamic acid, a potential degradation product of pemetrexed, and for the quantification of pemetrexed itself. This is an ion-pairing, reversed-phase method. The column was a Synergi MAX-RP C12 4 µm (150 mm x 4.6 mm). The mobile phase was 1 mM tridecafluoroheptanoic acid in aqueous solution and acetonitrile under gradient elution mode. L-Glutamic acid was detected by ELSD, and pemetrexed by UV at 254 nm. Good resolution was achieved between pemetrexed and L-glutamic acid. The HPLC method was validated according to SFSTP and ICH guidelines, and applied the accuracy profile procedure with a five-level validation experimental design. For pemetrexed, the decision criteria selected consisted of the acceptability limits (±3%) and the proportion of results within the calculated tolerance intervals (95%). In conclusion, the proposed analytical procedures were validated over the selected validation domains for L-glutamic acid (0.005-0.025 mg/mL) and pemetrexed (0.4-0.6 mg/mL) and shown to provide a very effective method.


Assuntos
Cromatografia de Fase Reversa/métodos , Estabilidade de Medicamentos , Glutamatos/química , Guanina/análogos & derivados , Luz , Raios Ultravioleta , Calibragem , Cromatografia Líquida de Alta Pressão , Ácido Glutâmico/análise , Guanina/química , Íons , Limite de Detecção , Pemetrexede , Reprodutibilidade dos Testes , Espalhamento de Radiação , Sensibilidade e Especificidade , Volatilização
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