RESUMEN
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.
Asunto(s)
Ésteres , Hidrogeles , Hidrogeles/química , Polímeros/química , Ácidos Borónicos/químicaRESUMEN
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.
Asunto(s)
Benzofenantridinas/farmacología , Fibronectinas/metabolismo , Adhesiones Focales/efectos de los fármacos , Integrina beta1/metabolismo , Animales , Western Blotting , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 2 de Adhesión Focal/metabolismo , Adhesiones Focales/metabolismo , Integrina beta1/genética , Leucemia L1210/genética , Leucemia L1210/metabolismo , Leucemia L1210/patología , Leucemia Linfoide/genética , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patología , Microdominios de Membrana/efectos de los fármacos , Microdominios de Membrana/metabolismo , Ratones , Microscopía Confocal , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tirosina/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos , Benzofuranos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzofuranos/síntesis química , Benzofuranos/química , Benzofuranos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/patología , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Acetofenonas/síntesis química , Alcoholes/química , Compuestos Alílicos/síntesis química , Benzopiranos/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Calophyllum/químicaRESUMEN
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.
