Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer's disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds' potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
- MeSH
- berberin chemie metabolismus farmakologie MeSH
- cholinesterasové inhibitory chemie metabolismus farmakologie MeSH
- cholinesterasy metabolismus MeSH
- hematoencefalická bariéra metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- prolyloligopeptidasy antagonisté a inhibitory MeSH
- racionální návrh léčiv * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Plant secondary metabolism evolved in the context of highly organized and differentiated cells and tissues, featuring massive chemical complexity operating under tight environmental, developmental and genetic control. Biotechnological demand for natural products has been continuously increasing because of their significant value and new applications, mainly as pharmaceuticals. Aseptic production systems of plant secondary metabolites have improved considerably, constituting an attractive tool for increased, stable and large-scale supply of valuable molecules. Surprisingly, to date, only a few examples including taxol, shikonin, berberine and artemisinin have emerged as success cases of commercial production using this strategy. The present review focuses on the main characteristics of plant specialized metabolism and their implications for current strategies used to produce secondary compounds in axenic cultivation systems. The search for consonance between plant secondary metabolism unique features and various in vitro culture systems, including cell, tissue, organ, and engineered cultures, as well as heterologous expression in microbial platforms, is discussed. Data to date strongly suggest that attaining full potential of these biotechnology production strategies requires being able to take advantage of plant specialized metabolism singularities for improved target molecule yields and for bypassing inherent difficulties in its rational manipulation.
- MeSH
- artemisininy izolace a purifikace metabolismus MeSH
- axenická kultura MeSH
- berberin izolace a purifikace metabolismus MeSH
- biologické přípravky izolace a purifikace metabolismus MeSH
- biotechnologie metody MeSH
- buněčné kultury MeSH
- fytonutrienty biosyntéza izolace a purifikace MeSH
- metabolické inženýrství metody MeSH
- naftochinony izolace a purifikace metabolismus MeSH
- paclitaxel biosyntéza izolace a purifikace MeSH
- rostlinné buňky chemie metabolismus MeSH
- rostliny chemie genetika metabolismus MeSH
- sekundární metabolismus MeSH
- techniky tkáňových kultur MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
