RESUMO
2-Amino-7-fluorophenazine 5,10-dioxide (FNZ) is a bioreducible prodrug, poorly soluble in water, with potential anticancer activity on hypoxic-tumors. This poor solubility limits its potential applications in clinic. Amphiphilic pristine polymeric micelles (PMs) based on triblock copolymers Pluronic® and Tetronic®, glycosylated derivatives and their mixtures with preformed-liposomes (LPS), were analyzed as strategies to improve the bioavailability of FNZ. FNZ encapsulations were performed and the obtaining nanostructures were characterized using UV-visible spectroscopy (UV-VIS), Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS). The most promising nanoformulations were analyzed for their potential toxicity and pharmacologically, at 20 mg/kg FNZ-doses, in a stage-IV murine metastatic-breast tumor model. The results revealed that the solubility of the encapsulated-FNZ increased up to 14 times and the analysis (UV-VIS, DLS and TEM) confirmed the interaction between vehicles and FNZ. In all the cases appropriate encapsulation efficiencies (greater than 75%), monodisperse nanometric particle sizes (PDI = 0.180-0.335), adequate Z-potentials (-1.59 to -26.4 mV), stabilities and spherical morphologies were obtained. The in vitro profile of FNZ controlled releases corresponded mainly to a kinetic Higuchi model. The in vitro/in vivo biological studies revealed non-toxicity and relevant tumor-weight diminution (up to 61%).
RESUMO
Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being-especially for glioblastomas-extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood-brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-ß inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.
RESUMO
Background: Carboranylanilinoquinazoline-hybrids, developed for boron neutron capture therapy, have demonstrated cytotoxicity against murine-glioma cells with EGFR-inhibition ability. In addition, their adequate aqueous/metabolic stabilities and ability to cross blood-brain barrier make them good leads as to become antiglioma drugs. Aim: Analyze drug-like properties of representative carboranylanilinoquinazolines. Materials & methods: To expand carboranylanilinoquinazolines therapeutic spectrum, we studied their ability to act against glioma-mammal cells, U-87 MG and other tyrosine kinase-overexpress cells, HT-29. Additionally, we predicted theoretically and studied experimentally drug-like properties, in other words, organization for economic cooperation and development-recommended toxicity-studies and, due to some aqueous-solubility problems, and vehicularization for oral and intravenous administrations. Conclusion: We have identified a promising drug-candidate with broad activity spectrum, appropriate drug-like properties, adequate toxicological behavior and able ability to be loaded in suitable vehicles.
Assuntos
Compostos de Anilina/química , Antineoplásicos/química , Neoplasias Encefálicas/radioterapia , Receptores ErbB/antagonistas & inibidores , Glioma/radioterapia , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Terapia por Captura de Nêutron de Boro/métodos , Linhagem Celular Tumoral , Sobrevivência Celular , Colesterol/química , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Fosfatidilcolinas/química , Poliaminas/química , Polietilenos/química , Polipropilenos/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/farmacologia , Solubilidade , ÁguaRESUMO
The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease.
Assuntos
Tolueno/análogos & derivados , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Macrófagos/efeitos dos fármacos , Camundongos , Esteróis/antagonistas & inibidores , Esteróis/biossíntese , Tolueno/síntese química , Tolueno/química , Tolueno/farmacologia , Tripanossomicidas/síntese química , Trypanosoma cruzi/metabolismoRESUMO
Highly potent bryostatin analogues which contain the complete bryostatin core structure have been synthesized using a pyran annulation approach as a key strategic element. The A ring pyran was assembled using a pyran annulation reaction between a C1-C8 hydroxy allylsilane and an aldehyde comprising C9-C13. This pyran was transformed to a new hydroxy allylsilane and then coupled with a preformed C ring aldehyde subunit in a second pyran annulation, with concomitant formation of the B ring. This tricyclic intermediate was elaborated to bryostatin analogues which displayed nanomolar to subnanomolar affinity for PKC, but displayed properties indistinguishable from a phorbol ester in a proliferation/attachment assay.
Assuntos
Briostatinas/síntese química , Piranos/química , Acetato de Tetradecanoilforbol/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Briostatinas/químicaRESUMO
[reaction: see text] The development of an approach leading to the total synthesis of dactylolide is described. The key features of this route include a catalytic asymmetric allylation, a diastereoselective pyran annulation, and a Horner-Wadsworth-Emmons macrocyclization.