RESUMO
Dynamic hydrogels are viscoelastic materials that can be designed to be self-healing, malleable, and injectable, making them particularly interesting for a variety of biomedical applications. To design dynamic hydrogels, dynamic covalent crosslinking reactions are attracting increasing attention. However, dynamic covalent hydrogels tend to swell, and often lack stability. Boronate ester-based hydrogels, which result from the dynamic covalent reaction between a phenylboronic acid (PBA) derivative and a diol, are based on stable precursors, and can therefore address these limitations. Yet, boronate ester formation hardly occurs at physiological pH. To produce dynamic covalent hydrogels at physiological pH, we performed a molecular screening of PBA derivatives in association with a variety of diols, using hyaluronic acid as a polymer of interest. The combination of Wulff-type PBA (wPBA) and glucamine stood out as a unique couple to obtain the desired hydrogels. We showed that optimized wPBA/glucamine hydrogels are minimally- to non-swelling, stable long term (over months), tunable in terms of mechanical properties, and cytocompatible. We further characterized their viscoelastic and self-healing properties, highlighting their potential for biomedical applications.
Assuntos
Ésteres , Hidrogéis , Hidrogéis/química , Polímeros/química , Ácidos Borônicos/químicaRESUMO
BACKGROUND: Leukemic cell adhesion to proteins of the bone marrow microenvironment provides signals which control morphology, motility and cell survival. We described herein the ability of ethoxyfagaronine (etxfag), a soluble synthetic derivative of fagaronine, to prevent leukemic cell adhesion to fibronectin peptide (FN/V). METHODS: Phosphorylation of fak and pyk2 were evaluated by immunoblotting. Labelled proteins were localized by confocal microscopy. PI 3-kinase activity was evaluated by in vitro kinase assay. RESULTS: Subtoxic concentration of etxfag reduced L1210 cell adhesion to FN/V dependently of ß1 integrin engagement. Etxfag impaired FN-dependent formation of ß1 clustering without modifying ß1 expression at the cell membrane. This was accompanied by a decrease of focal adhesion number, a diminution of fak and pyk2 phosphorylation at Tyr-576, Tyr-861 and Tyr-579, respectively leading to their dissociations from ß1 integrin and inhibition of PI 3-kinase activity. Etxfag also induced a cell retraction accompanied by a redistribution of phosphorylated fak and pyk2 in the perinuclear region and lipid raft relocalization. CONCLUSION: Through its anti-adhesive potential, etxfag, combined with conventional cytotoxic drugs could be potentially designed as a new anti-leukemic drug.
Assuntos
Benzofenantridinas/farmacologia , Fibronectinas/metabolismo , Adesões Focais/efeitos dos fármacos , Integrina beta1/metabolismo , Animais , Western Blotting , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Adesões Focais/metabolismo , Integrina beta1/genética , Leucemia L1210/genética , Leucemia L1210/metabolismo , Leucemia L1210/patologia , Leucemia Linfoide/genética , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Camundongos , Microscopia Confocal , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tirosina/metabolismoRESUMO
The synthesis of 2-isopropenyl-2,3-dihydrobenzofuranic enantioisomers is described. Ortho-(2-hydroxy-3-methyl-but-3-enyl)phenol synthons are used as precursors to these structures. In vitro antitumor activity against a non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) of these enantioisomers has been investigated.
Assuntos
Antineoplásicos , Benzofuranos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/patologia , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The synthesis of benzopyranic simplified analogues of dibenzopyranic natural compounds is described, together with the access to a precursor of a new furobenzopyranic natural product. These natural products have anti-cancer activity. The 1,3-diacetoxy-2-acetyl-4-(3-hydroxy-3-methylbut-1-enyl)benzene synthone is used as a common precursor to these structures.
Assuntos
Acetofenonas/síntese química , Álcoois/química , Compostos Alílicos/síntese química , Benzopiranos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Calophyllum/químicaRESUMO
Eight new 4-phenylfuranocoumarins (1-8) have been isolated from the stem bark and the fruits of Calophyllum dispar, together with three known coumarins. The structures of 1-8 were established by means of spectroscopic analysis, including extensive 2D NMR studies. Some of these furanocoumarins exhibited significant cytotoxic activity against KB cells.