The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.
- MeSH
- antiflogistika chemická syntéza chemie farmakologie toxicita MeSH
- azepiny chemická syntéza chemie farmakologie MeSH
- buněčná adheze účinky léků MeSH
- cévní endotel účinky léků imunologie MeSH
- endoteliální buňky pupečníkové žíly (lidské) MeSH
- epoxidové sloučeniny chemická syntéza chemie farmakologie MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem antagonisté a inhibitory MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie toxicita MeSH
- lidé MeSH
- neutrofily účinky léků imunologie MeSH
- racionální návrh léčiv MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus patologie MeSH
- antigeny bakteriální terapeutické užití MeSH
- azepiny chemie terapeutické užití MeSH
- bakteriální proteiny terapeutické užití MeSH
- inhibitory proteinkinas chemie terapeutické užití MeSH
- lidé MeSH
- methylenová modř chemie terapeutické užití MeSH
- neurony metabolismus MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory metabolismus MeSH
- proteiny tau antagonisté a inhibitory metabolismus MeSH
- pyrazoly chemie terapeutické užití MeSH
- pyridiny chemie terapeutické užití MeSH
- pyrroly chemie terapeutické užití MeSH
- staurosporin chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancer therapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumor drugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview of development over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential in applications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and development of combined chemotherapy is discussed.
- MeSH
- alkaloidy chemie terapeutické užití MeSH
- anthrachinony chemie terapeutické užití MeSH
- azepiny chemie terapeutické užití MeSH
- aziridiny chemie terapeutické užití MeSH
- DNA chemie metabolismus MeSH
- komplexní sloučeniny chemie terapeutické užití MeSH
- lidé MeSH
- mechlorethamin chemie terapeutické užití MeSH
- nádory farmakoterapie MeSH
- oprava DNA MeSH
- protinádorové látky chemie terapeutické užití MeSH
- reagencia zkříženě vázaná chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The development in the field of pharmaceutical dosage forms results in the discovery of additional highly sophisticated drug delivery systems that allow maintaining a constant level of the active substance in an organism. Transdermal therapeutic systems are an excellent alternative to conventional pharmaceutical dosage forms. However, the application of transdermal drug delivery faces the problem of insufficient or no penetration of active pharmaceutical substances through the skin. This review article describes the possible fundamental mechanisms of penetration through the skin barrier and refers to the classification of skin penetration enhancers. Azone-like enhancers are considered in detail and classified according to their structure on the basis of medicinal chemistry approaches. The article also provides a review of original transdermal penetration enhancers prepared in our laboratory and discusses the relationship between the chemical structure of the described Azone analogues and their penetration activity (SAR/QSAR).
- MeSH
- aplikace kožní MeSH
- azepiny chemie metabolismus farmakologie MeSH
- kožní absorpce účinky léků MeSH
- kůže anatomie a histologie účinky léků MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- lidé MeSH
- racionální návrh léčiv * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
