RESUMO
A peptide Claisen rearrangement is used as key step to generate a tetrapeptide with a C-terminal double unsaturated side chain. Activation and cyclization give direct access to cyclopeptides related to naturally occurring histone deacetylase (HDAC) inhibitors Cyl-1 and Cyl-2. Late stage modifications on the unsaturated amino acid side chain allow the introduction of functionalities which might coordinate to metal ions in the active center of metalloproteins, such as histone deacetylases.
RESUMO
Combination chemotherapy has proven to be a favorable strategy to treat acute leukemia. However, the introduction of novel compounds remains challenging and is hindered by a lack of understanding of their mechanistic interactions with established drugs. In the present study, we demonstrate a highly increased response of various acute leukemia cell lines, drug-resistant cells and patient-derived xenograft cells by combining the recently introduced protein disulfide isomerase inhibitor PS89 with cytostatics. In leukemic cells, a proteomics-based target fishing approach revealed that PS89 affects a whole network of endoplasmic reticulum homeostasis proteins. We elucidate that the strong induction of apoptosis in combination with cytostatics is orchestrated by the PS89 target B-cell receptor-associated protein 31, which transduces apoptosis signals at the endoplasmic reticulum -mitochondria interface. Activation of caspase-8 and cleavage of B-cell receptor-associated protein 31 stimulate a pro-apoptotic crosstalk including release of calcium from the endoplasmic reticulum and an increase in the levels of reactive oxygen species resulting in amplification of mitochondrial apoptosis. The findings of this study promote PS89 as a novel chemosensitizing agent for the treatment of acute leukemia and uncovers that targeting the endoplasmic reticulum - mitochondrial network of cell death is a promising approach in combination therapy.
Assuntos
Citostáticos/farmacologia , Retículo Endoplasmático/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia , Camundongos , Modelos Biológicos , Proteoma , Proteômica/métodos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Peptide modification reactions, e.g., via palladium-catalyzed allylic alkylations, are useful tools for the synthesis of peptides containing interesting nonproteinogenic amino acids, which are often essential for the biological activity of natural products and drugs. Herein we report the utilization of such modification reactions in the first total synthesis of trapoxin A, a naturally occurring tetrapeptidic histone deacetylase (HDAC) inhibitor.
Assuntos
Ascomicetos/química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Peptídeos/química , Peptídeos/síntese química , Catálise , Técnicas de Química Sintética , Paládio/químicaRESUMO
Chelate enolate Claisen rearrangements are powerful reactions for constructing amino acid scaffolds. They generally proceed via chair-like transition states with excellent transfer of stereogenic information. Utilizing this reaction in natural product synthesis gives access to non-proteinogenic amino acids such as (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe), the unusual amino acid of a series of histone deacetylase inhibitors (HDACi). Herein the first total synthesis of Cyl-1, a cyclotetrapeptide from Cylindrocladium scoparium, is described.
Assuntos
Aminoácidos/síntese química , Produtos Biológicos/síntese química , Inibidores de Histona Desacetilases/síntese química , Hypocreales/química , Peptídeos Cíclicos/síntese química , Aminoácidos/química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Peptídeos Cíclicos/químicaRESUMO
Resistance to chemotherapeutic agents represents a major challenge in cancer research. One approach to this problem is combination therapy, the application of a toxic chemotherapeutic drug together with a sensitizing compound that addresses the vulnerability of cancer cells to induce apoptosis. Here we report the discovery of a new compound class (T8) that sensitizes various cancer cells towards etoposide treatment at subtoxic concentrations. Proteomic analysis revealed protein disulfide isomerase (PDI) as the target of the T8 class. In-depth chemical and biological studies such as the synthesis of optimized compounds, molecular docking analyses, cellular imaging, and apoptosis assays confirmed the unique mode of action through reversible PDI inhibition.