RESUMO
Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate was 63.0% (P < 0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.
Assuntos
Antineoplásicos , Irídio , Mitocôndrias , Humanos , Irídio/química , Irídio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Animais , Células Hep G2 , Camundongos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Apoptose/efeitos dos fármacos , Oxiquinolina/farmacologia , Oxiquinolina/química , Oxiquinolina/análogos & derivados , Camundongos Endogâmicos BALB C , Mitofagia/efeitos dos fármacos , Camundongos NusRESUMO
Radiation therapy is one of the most common treatments for cancer. However, enhancing tumors' radiation sensitivity and overcoming tolerance remain a challenge. Previous studies have shown that the Ras signaling pathway directly influences tumor radiation sensitivity. Herein, we designed a series of Ras-targeting stabilized peptides, with satisfactory binding affinity (KD = 0.13 µM with HRas) and good cellular uptake. Peptide H5 inhibited downstream phosphorylation of ERK and increased radio-sensitivity in HeLa cells, resulting in significantly reduced clonogenic survival. The stabilized peptides, designed with an N-terminal nucleation strategy, acted as potential radio-sensitizers and broadened the applications of this kind of molecule. This is the first report of using stabilized peptides as radio-sensitizers, broadening the applications of this kind of molecule.
Assuntos
Peptídeos , Tolerância a Radiação , Proteínas ras , Humanos , Peptídeos/química , Peptídeos/farmacologia , Células HeLa , Tolerância a Radiação/efeitos dos fármacos , Proteínas ras/metabolismo , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Sobrevivência Celular/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/radioterapiaRESUMO
An HCBP1 peptide-ruthenium conjugate (Ru-ß-Ala-FQHPSFI) as a potential candidate for targeted therapy of hepatoma was synthesized. Ru-ß-Ala-FQHPSFI shows drastically enhanced cytotoxicity and high selectivity for hepatoma cells versus noncancer liver cells. Raman imaging shows that this peptide-based drug can be taken up well by the hepatoma cells compared with the bare ruthenium complex (Ru) and the opposite sequence peptide-ruthenium conjugate (Ru-ß-Ala-IFSPHQF). This study presents a new strategy for the construction of tumor-targeting metal-based anticancer therapeutics.
Assuntos
Carcinoma Hepatocelular/patologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Neoplasias Hepáticas/patologia , Oligopeptídeos/química , Rutênio/química , Sequência de Aminoácidos , Células Hep G2 , HumanosRESUMO
Insulin-degrading enzyme (IDE) plays a critical role in both the proteolytic degradation and inactivation of insulin. The exploration of novel IDE inhibitors could aid in the study of novel therapeutics for type-2 diabetes. Herein, we report a hypothesized stabilized ß-hairpin peptide that can efficiently inhibit the enzymatic activity of IDE. The resulting stabilized peptide B35 is demonstrated to activate the AKT phosphorylation pathway in skeletal muscle cells and is shown to slow insulin degradation. An 80 mg kg-1 intraperitoneal (i.p.) injection of the stabilized ß-hairpin peptide B35 is demonstrated to improve glucose tolerance during an oral glucose tolerance test in obese mouse model. We note that this stabilized peptide exhibited negligible cytotoxicity in both in vitro and in vivo assays, even at high concentrations (300 µM). This study suggests that IDE peptide inhibitors could function as potentially meaningful candidates for the development of type-2 diabetes therapeutics.
Assuntos
Modelos Animais de Doenças , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Obesidade/tratamento farmacológico , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Teste de Tolerância a Glucose , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismoRESUMO
Estrogen receptor α (ERα) is a crucial target for ERα positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERα. However, significant percentage of patients developed cancer relapse with drug-resistance. ERα peptidomimetic modulators have been considered as promising treatments for drug resistant breast cancers as they are targeting ERα-coactivator interacting interface instead of the ligand binding pocket of ERα. Herein, we reviewed the recent development of ERα peptidomimetics antagonists.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/antagonistas & inibidores , Peptidomiméticos/antagonistas & inibidores , Alcaloides de Vinca/uso terapêutico , Animais , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Peptidomiméticos/metabolismo , Alcaloides de Vinca/químicaRESUMO
Antimicrobial peptides (AMPs) are short cationic peptides with a high affinity for membranes and emerged as a promising therapeutic approach with potential for treating infectious diseases. Chemical stabilization of short peptides proved to be a successful approach for enhancing their bio-physical properties. Herein, we designed and synthesized a panel of conformationally constrained antimicrobial peptides with either α-helical or ß-hairpin conformation using templating strategies. These synthetic short constrained peptides possess different topological distributions of hydrophobic and hydrophilic residues and displayed distinct antimicrobial activity. Notably, the conformationally constrained α-helical peptides displayed a faster internalization into the bacteria cells compared to their ß-hairpin analogues. These synthetic short constrained peptides showed killing effects on a broad spectrum of microorganisms mainly through pore formation and membrane damage which provided a potentially promising skeleton for the next generation of stabilized antimicrobial peptides.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Desenho de Fármacos , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Bactérias/citologia , Infecções Bacterianas/tratamento farmacológico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Secundária de ProteínaRESUMO
We have developed a general peptide macrocyclization strategy that involves a facile and chemoselective methionine bis-alkylation/dealkylation process. This method provides a straightforward and easy approach to generate cyclic peptides with tolerances of all amino acids (including Cys), variable loop sizes, and different linkers. The Met bis-alkylation we apply in this strategy yields two additional on-tether positive charges that could assist in the cellular uptake of the peptides. Notably, the bis-alkylated peptide could be reduced to release the original peptide both in vitro and within cellular environments. This strategy provides an intriguing and facile traceless post-peptide-synthesis modification with enhanced cellular uptakes. Peptides constructed with this method could be utilized to zero in on various protein targets or to achieve other goals, such as drug delivery.
RESUMO
A fluorescent dye, FEB, with high fluorescence quantum yield for tumour imaging is reported. FEB dyes can be efficiently synthesized in three steps and then easily modified with either PEG or PEG-iRGD to yield FEB-2000 or FEB-2000-iRGD, respectively. Both modified dyes showed negligible toxicity and were thus able to be adopted for in vivo tumour imaging. PEG modification endowed the dye FEB-2000 with both long circulating times and good tumour targeting properties in a MDA-MB-231 xenograft model. Further conjugation with iRGD to generate FEB-2000-iRGD showed minimal targeting enhancement. These results provide a template for the efficient preparation of FEB dyes for use in tumour imaging, thus providing a foundation for future modifications.