(1) Background: To compare the effect of selected triterpenoids with their structurally resembling derivatives, designing of the molecular ribbons was targeted to develop compounds with selectivity in their pharmacological effects. (2) Methods: In the synthetic procedures, Huisgen 1,3-dipolar cycloaddition was applied as a key synthetic step for introducing a 1,2,3-triazole ring as a part of a junction unit in the molecular ribbons. (3) Results: The antimicrobial activity, antiviral activity, and cytotoxicity of the prepared compounds were studied. Most of the molecular ribbons showed antimicrobial activity, especially on Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus faecalis, with a 50-90% inhibition effect (c = 25 µg·mL-1). No target compound was effective against HSV-1, but 8a displayed activity against HIV-1 (EC50 = 50.6 ± 7.8 µM). Cytotoxicity was tested on several cancer cell lines, and 6d showed cytotoxicity in the malignant melanoma cancer cell line (G-361; IC50 = 20.0 ± 0.6 µM). Physicochemical characteristics of the prepared compounds were investigated, namely a formation of supramolecular gels and a self-assembly potential in general, with positive results achieved with several target compounds. (4) Conclusions: Several compounds of a series of triterpenoid molecular ribbons showed better pharmacological profiles than the parent compounds and displayed certain selectivity in their effects.
- Publikační typ
- časopisecké články MeSH
The comparative study of new proteasome inhibitors based on salicylic acid-modified pseudo-tripeptides terminated with aldehyde or vinylsulfone is presented. We described the synthesis of 11 pairs of pseudopeptides and their properties related to the proteasome inhibition were determined. The effects of integrated amino acids (combinations of leucine, phenylalanine, tryptophan, proline, cyclohexylalanine or norleucine residues) on the activity of the proteasome were investigated. Compounds preferentially inhibited the chymotrypsin β5-subunit of the proteasome in cell-based assays compared with the β1- and β2-subunits, with IC50 values in mid-nanomolar ranges being obtained for the most active members. Our comparative study demonstrated that aldehydes were able to inhibit the proteasome in cells more effectively than vinylsulfones. These results were corroborated by the accumulation of polyubiquitinated proteins in treated cells, GFP accumulation in a reporter cell line and the ability of new compounds to induce apoptotic cell death.
- MeSH
- aldehydy chemie farmakologie MeSH
- inhibitory proteasomu chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- peptidy chemie farmakologie MeSH
- proteasomový endopeptidasový komplex metabolismus MeSH
- sulfony chemie farmakologie MeSH
- vinylové sloučeniny chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro- to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development.
- MeSH
- antitumorózní látky chemická syntéza metabolismus farmakologie MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory metabolismus MeSH
- imidazoly chemie metabolismus farmakologie MeSH
- inhibitory proteinkinas chemická syntéza metabolismus farmakologie MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- pyrimidiny chemie metabolismus farmakologie MeSH
- simulace molekulární dynamiky MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
