Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15-38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.
- MeSH
- adamantan chemie MeSH
- inzulin analogy a deriváty chemická syntéza metabolismus MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- kvarterní struktura proteinů MeSH
- lidé MeSH
- prolin chemie MeSH
- receptor inzulinu chemie metabolismus MeSH
- simulace molekulární dynamiky MeSH
- stabilita proteinů MeSH
- stereoizomerie MeSH
- techniky syntézy na pevné fázi MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.
- MeSH
- adamantan chemie MeSH
- antitumorózní látky chemie farmakologie MeSH
- beta-cyklodextriny chemie MeSH
- buňky K562 MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- puriny chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure-activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.
- MeSH
- adamantan analogy a deriváty chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- buněčná smrt účinky léků MeSH
- buňky MDCK MeSH
- diferenční termická analýza MeSH
- krystalografie rentgenová MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- lidé MeSH
- metoda nejmenších čtverců MeSH
- molekulární konformace MeSH
- Orthomyxoviridae účinky léků MeSH
- počítačová simulace * MeSH
- proteinové domény MeSH
- proteiny virové matrix chemie MeSH
- psi MeSH
- rimantadin krev chemie MeSH
- simulace molekulového dockingu MeSH
- stabilita léku MeSH
- teplota MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. EXPERIMENTAL APPROACH: IRI was induced in uninephrectomized male rats by renal artery clamping for 30 min. The sham group was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p.o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg·kg-1·day-1), vildagliptin (8 mg·kg-1·day-1) and sitagliptin (30 mg·kg-1·day-1). An additional group received sitagliptin until study end (before IRI: 30 mg·kg-1·day-1; after IRI: 15 mg·kg-1·day-1). KEY RESULTS: Plasma-active glucagon-like peptide type 1 (GLP-1) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP-1 plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. CONCLUSIONS AND IMPLICATIONS: In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage.
- MeSH
- adamantan aplikace a dávkování analogy a deriváty chemie farmakologie MeSH
- dipeptidylpeptidasa 4 metabolismus MeSH
- inhibitory dipeptidylpeptidasy 4 aplikace a dávkování chemie farmakologie MeSH
- krysa rodu rattus MeSH
- ledviny účinky léků metabolismus patologie MeSH
- linagliptin aplikace a dávkování chemie farmakologie MeSH
- molekulární struktura MeSH
- nitrily aplikace a dávkování chemie farmakologie MeSH
- potkani Wistar MeSH
- pyrrolidiny aplikace a dávkování chemie farmakologie MeSH
- reperfuzní poškození farmakoterapie metabolismus patologie MeSH
- sitagliptin fosfát aplikace a dávkování chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
To investigate structure-function relationships of cytochromes P450 (CYP), 3-azidiamantane was employed for photoaffinity labeling of rabbit microsomal CYP2B4. Four diamantane labeled tryptic fragments were identified by mass spectrometry and sequencing: peptide I (Leu359-Lys373), peptide II (Leu30-Arg48), peptide III (Phe127-Arg140), and peptide IV (Arg434-Arg443). Their positions were projected into CYP2B4 model structures and compared with substrate binding sites, proposed by docking of diamantane. We identified novel binding regions outside the active site of CYP2B4. One of them, defined with diamantane modified Arg133, marks a possible entrance to the active site from the heme proximal face. In addition to crystal structures of CYP2B4 chimeras and molecular dynamics simulations, our data of photoaffinity labeling of the full CYP2B4 molecule provide further insight into functional and structural aspects of substrate binding.
- MeSH
- adamantan analogy a deriváty chemie MeSH
- aromatické hydroxylasy chemie ultrastruktura MeSH
- chemické modely MeSH
- financování organizované MeSH
- fluorescenční mikroskopie metody MeSH
- fotochemie metody MeSH
- konformace proteinů MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- substrátová specifita MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- MeSH
- adamantan analogy a deriváty chemie metabolismus MeSH
- aromatické hydroxylasy antagonisté a inhibitory genetika metabolismus MeSH
- cytochrom P-450 CYP2B1 antagonisté a inhibitory genetika metabolismus MeSH
- finanční podpora výzkumu jako téma MeSH
- inhibitory enzymů farmakologie chemie metabolismus MeSH
- králíci MeSH
- krysa rodu rattus MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
Vývoj neuroprotektivních léčiv je v současné době zaměřen na látky inhibující neurotransmisi zprostředkovanou excitačními aminokyselinami a na látky s antioxidačními vlastnostmi. Nízkoafinitní antagonista NMDA receptorů memantin, dimethyl-derivát amantadinu, je nadějnou látkou tohoto typu. Článek podává přehled o memantinu jako novém léčivu, které by mohlo být využito u četných poruch CNS.
The development of neuroprotective agents is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exert antioxidant properties. Low affinity NMDA receptor antagonist memantine, dimethyl derivative of amantadine, is a promising compound of this type. The aim of this article is to give a review of memantine as a new therapeutic agent in numerous CNS disorders.
- Klíčová slova
- AKATIONOL,
- MeSH
- adamantan aplikace a dávkování chemie terapeutické užití MeSH
- demence farmakoterapie MeSH
- glutamátové receptory účinky léků MeSH
- lidé MeSH
- memantin MeSH
- nemoci mozku farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- adamantan analýza chemie MeSH
- inhibitory enzymů analýza chemie MeSH
- jaterní mikrozomy chemie MeSH
- magnetická rezonanční spektroskopie diagnostické užití metody ultrasonografie MeSH
- systém (enzymů) cytochromů P-450 MeSH
- vysokoúčinná kapalinová chromatografie metody přístrojové vybavení využití MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
