Přírodní látky produkované rostlinami představují významný zdroj nových léčivých substancí. Tento článek je zaměřen na popis antimikrobiální, antivirální a cytotoxické aktivity syntetizovaných derivátů betulonové a platanové kyseliny, zejména jejich oximových derivátů. Cílem článku je poskytnout přehled zmíněných aktivit těchto derivátů a jejich možného využití v oblasti léčby infekčních či nádorových onemocnění.
Natural substances produced by plants represent an important source of new medicinal products. This article is focused on the description of the antimicrobial, antiviral, and cytotoxic activity of the synthesized derivatives of betulonic and platanic acids, especially their oxime-based derivatives. It is also aimed at providing overview of the possible use of these derivatives in the treatment of infectious or cancer diseases.
- MeSH
- amidy chemie farmakologie MeSH
- antibakteriální látky MeSH
- antivirové látky MeSH
- kyselina betulinová chemie farmakologie MeSH
- lidé MeSH
- oximy chemie farmakologie MeSH
- pentacyklické triterpeny chemie farmakologie MeSH
- protinádorové látky MeSH
- triterpeny * chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
In this work, a large set of betulinic acid derivatives modified with various aromatic substituents at the position C-3 were prepared via Suzuki-Myiaura cross-coupling. All compounds were tested for their in vitro cytotoxic activity in 8 cancer and 2 healthy cell lines. Derivatives 6h, 6i, and 6o had the lowest IC50 in the CCRF-CEM cell line (0.69-4.0 μM) and had high selectivity. In addition, 6h and 6i also showed significant activity in daunorubicin-resistant CEM and taxol-resistant K562 cell lines; therefore, they were selected for the evaluation of the mechanism of action. First, the effect of 6h, 6i, and 6o on cell death induction was studied. To our surprise, we have not detected almost any apoptotic cells, even following a long-time exposure of CCRF-CEM cells to the compounds. On the other hand, a dramatic cell number decrease was observed, proportional to the time of the compound's exposure. Based on this data it was concluded that the effect of compounds is cytostatic rather than cytotoxic, which was further confirmed by subsequent studies of the impact of 6h, 6i, and 6o on the cell cycle. Detailed cell cycle analysis revealed a block in the G1 phase accompanied by reduced expression of phosphorylated forms of the RB protein as well as cyclin A protein. Evaluation of the pharmacological properties of the most promising compounds revealed their high stability in the presence of phosphate buffer, human plasma, and microsomes and limited permeability determined using permeability through artificial membrane (PAMPA) and cell permeability assay: Caco-2 and MDCK-MDR1 cell lines. Compounds 6h, 6i, and 6o were selected for further drug development; their cytostatic effect may be advantageous in this process since we expect fewer non-specific interactions and toxicity than in highly cytotoxic compounds. In addition, the activity of 6h and 6i against resistant CEM-DNR and K562-TAX leukemic cell lines makes them promising as a possible future alternative to currently used therapies.
- MeSH
- apoptóza MeSH
- Caco-2 buňky MeSH
- cytostatické látky * farmakologie MeSH
- fenotyp MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory * MeSH
- pentacyklické triterpeny farmakologie MeSH
- protinádorové látky * farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC50 and almost complete inhibition at 5 × IC50. Interestingly, compound 4.39 at 5 × IC50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug.
- MeSH
- alkadieny chemická syntéza chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- pentacyklické triterpeny chemie farmakologie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- psi MeSH
- screeningové testy protinádorových léčiv MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Osteosarcoma (OS), a severe malignant bone tumour, usually occurs in adolescents and children and has a poor prognosis. Asiatic acid (AA), an active component isolated from Centella asiatica (L.) Urb., exhibits appreciable anti-oxidant and anti-tumour activities. So far, the effects and underlying mechanisms of AA against OS have not been clarified. Here, we explored the anti-tumour effects of AA against human OS and the involved mechanism mediating its actions. To evaluate effects of AA on the cell proliferation of human OS cells, cell viability and colony formation assays were performed. Flow cytometry was used to evaluate apoptosis in OS cells exposed to AA and mitochondrial membrane potential. Western blotting and RT-PCR were applied to determine expression of the relevant proteins and their mRNA levels. Our explorations showed that AA inhibits proliferation of human OS cells in a concentration- and time-dependent manner, and induces apoptosis of OS cells by the intrinsic (mitochondrial) pathway. Importantly, we found that inhibition of the AA-induced phosphorylation of JAK2/STAT3 signalling molecules and the decrease in MCL-1 contributed to the anti-tumour efficacy of AA. Collectively, our results suggest that AA could evoke mitochondrial- induced apoptosis in human OS cells by suppression of the JAK2/STAT3 pathway and MCL-1 expression. These results strongly demonstrate that AA could be a potential anti-tumour agent for OS treatment.
Adhesion of bacteria to epithelial tissue is an essential step in the progression of the urinary tract infections. Reduction of virulence factors responsible for microbial attachment may help to decrease or inhibit colonization of the host organism by pathogens. In the age of increasing bacterial antibiotic resistance, more and more attention is being paid to the use of plants and/or their bioactive components in the prevention and treatment of human infections. Asiatic acid (AA) and ursolic acid (UA), two plant secondary metabolites, were used as potential antibacterial agents. The current study aimed to determine the possible impact of AA and UA on morphology, hydrophobicity, and adhesion of clinical uropathogenic Escherichia coli strains (UPEC) to the uroepithelial cells. Our work describes for the first time the effects exerted by AA and UA on virulence factors of UPECs. The impact of both acids on the cell surface hydrophobicity of the investigated strains was very weak. The results clearly show the influence of AA and UA on the presence of P fimbriae and curli fibers, morphology of the UPECs cells and their adhesion to epithelium; however, some differences between activities of AA and UA were found.
- MeSH
- antibakteriální látky farmakologie MeSH
- bakteriální adheze účinky léků MeSH
- epitelové buňky cytologie mikrobiologie MeSH
- faktory virulence MeSH
- fylogeneze MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- pentacyklické triterpeny farmakologie MeSH
- rostlinné extrakty farmakologie MeSH
- sekvenční analýza DNA MeSH
- triterpeny farmakologie MeSH
- uropatogenní Escherichia coli účinky léků růst a vývoj MeSH
- urotel cytologie mikrobiologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
