RESUMO
Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.
Assuntos
Glutationa Peroxidase/antagonistas & inibidores , Tiepinas/química , Tiepinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Glutationa Peroxidase GPX1RESUMO
A novel class of glutathione peroxidase 1 (GPx1) inhibitors, namely tri- and tetracyclic pentathiepins, has been identified that is approximately 15 times more potent than the most active known GPx1 inhibitor, mercaptosuccinic acid. Enzyme kinetic studies with bovine erythrocyte GPx1 indicate that pentathiepins reversibly inhibit oxidation of the substrate glutathione (GSH). Moreover, no inhibition of superoxide dismutase, catalase, thioredoxin reductase or glutathione reductase was observed at concentrations that effectively inhibit GPx1. As well as potent enzyme inhibitory activity, the pentathiepins show strong anticancer activity in various human cancer cell lines, with IC50 values in a low-micromolar range. A representative tetracyclic pentathiepin causes the formation of reactive oxygen species in these cells, the fragmentation of nuclear DNA and induces apoptosis via the intrinsic pathway. Moreover, this pentathiepin leads to a rapid and strong loss of mitochondrial membrane potential in treated cancer cells. On the other hand, evidence for the induction of ferroptosis as a form of cell death was negative. These new findings show that pentathiepins possess interesting biological activities beyond those originally ascribed to these compounds.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glutationa Peroxidase/antagonistas & inibidores , Compostos Heterocíclicos/farmacologia , Sulfetos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutationa Peroxidase/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/química , Células Tumorais Cultivadas , Glutationa Peroxidase GPX1RESUMO
The thioetherification of heteroaryl chlorides is an essential synthetic methodology that provides access to bioactive drugs and agrochemicals. Due to their (actual or potential) industrial importance, the development of efficient and low-temperature protocols for accessing these compounds is a requirement for economic and ecologic reasons. A particular highly effective catalytic protocol using the Pd/PTABS system at only 50 °C was developed accordingly. The coupling between chloroheteroarenes and a variety of less reactive arylthiols and alkylthiols was carried out with a high efficiency. Heteroarenes of commercial relevance such as purines and pyrimidines were also found to be useful substrates for the reported transformation. The commercial drug Imuran (azathioprine) was synthesized as an example, and its preparation could be optimized. DFT studies were performed to understand the electronic effects of the tested ligands on the catalytic reaction.
RESUMO
The synthesis and catalytic applications of the highly water-soluble ligand 7-phospha-1,3,5-triaza-admantane butane sultonate (PTABS) has been described. The synthesized PTABS ligand along with palladium acetate exhibits excellent reactivity towards the amination reaction of 6-chloro-9-(ß-D-ribofuranosyl)-9H-purine at ambient temperature. This protocol offers an advantage over the previously published procedures for the amination of 6-chloropurine nucleoside furnishing 6-N-substituted adenosine analogues. The validation of the present strategy has been demonstrated via synthesis of a uracil-based, anti-diabetic drug alogliptin. © 2018 by John Wiley & Sons, Inc.
Assuntos
Hipoglicemiantes/síntese química , Paládio/química , Piperidinas/síntese química , Uracila/análogos & derivados , Aminação , Catálise , Hipoglicemiantes/química , Espectroscopia de Ressonância Magnética/métodos , Piperidinas/química , Solubilidade , Uracila/síntese química , Uracila/química , ÁguaRESUMO
9-Arylbenzo[b]quinolizinium derivatives were prepared with base-free Suzuki-Miyaura coupling reactions between benzo[b]quinolizinium-9-trifluoroborate and selected benzenediazonium salts. In addition, the Sonogashira coupling reaction between 9-iodobenzo[b]quinolizinium and the arylalkyne derivatives yielded four novel 9-(arylethynyl)benzo[b]quinolizinium derivatives under relatively mild reaction conditions. The 9-(N,N-dimethylaminophenylethynyl)benzo[b]quinolizinium is only very weakly emitting, but the emission intensity increases by a factor >200 upon protonation, so that this derivative may operate as pH-sensitive light-up probe. Photometric and fluorimetric titrations of duplex and quadruplex DNA to 9-(arylethynyl)benzo[b]quinolizinium derivatives revealed a significant binding affinity of these compounds towards both DNA forms with binding constants of Kb = 0.2-2.2 × 105 M-1.
RESUMO
The mol-ecular structure of the title compound, C8H11N3O, is nearly planar despite the chair conformation of the morpholine moiety. In the crystal, the mol-ecules form sheets parallel to the b axis, which are supported by non-classical hydrogen-bonding inter-actions between C-H functionalities and the O atom of morpholine and the 4-N atom of pyrazine, respectively. The title compound crystallizes in the monoclinic space group P21/c with four mol-ecules in the unit cell.