NMR spectroscopy is the key analytical method for determination of chemical structure and investigation of physico-chemical properties, such as non-covalent interac-tions, tautomeric equilibria or polymorphism. In this work, selected examples of using advanced NMR methods in structural analysis are discussed. (1) NMR spectroscopy with in situirradiation useful to monitor photochemical processes, (2) 31P NMR spectroscopy for reaction monitor-ing and probing stereochemistry and (3) solid-state NMR spectroscopy to investigate polymorphism.
Naphthoquinones isolated from Quambalaria cyanescens (quambalarines) are natural pigments possessing significant cytotoxic and antimicrobial properties. Determining the structure of naphthoquinone compounds is important for the understanding of their biological activities and the informed synthesis of related analogues. Identifying quambalarines is challenging, because they contain a hydroxylated naphthoquinone scaffold and have limited solubility. Here, we report a detailed structural study of quambalarine derivatives, which form strong intramolecular hydrogen bonds (IMHBs) that enable the formation of several tautomers; these tautomers may complicate structural investigation due to their fast interconversion. To investigate tautomeric equilibria and identify new quambalarines, we complemented the experimental NMR spectroscopy data with density functional theory (DFT) calculations.
- MeSH
- antiinfekční látky chemie izolace a purifikace farmakologie MeSH
- Basidiomycota chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- magnetická rezonanční tomografie MeSH
- molekulární struktura MeSH
- naftochinony chemie izolace a purifikace farmakologie MeSH
- protinádorové látky chemie izolace a purifikace farmakologie MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The nucleoside/nucleotide derived antiviral agents have been the most important components of antiviral therapy used in clinics. Recently, the focus of the medicinal chemists within this exciting research field has been affected mainly by the lack of effective therapies for the Hepatitis C virus (HCV) infection and several other "neglected" diseases caused by viruses such as Zika or Dengue. 2'-Methyl modified nucleosides and their monophosphate prodrugs (ProTides) have revolutionized the therapies for HCV in the last few years and, according to the latest research efforts, have also brought a promise for treatment of diseases caused by other members of Flaviviridae family. Here, we report on the design and synthesis of 5'-N and S modified ProTides derived from 2'-methyladenosine. We studied potential applicability of these derivatives as prodrugs of this archetypal antiviral compound.
- MeSH
- adenosin analogy a deriváty chemie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- dusík chemie MeSH
- Hepacivirus účinky léků MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- nukleotidy chemie metabolismus farmakologie MeSH
- prekurzory léčiv chemická syntéza chemie farmakologie MeSH
- síra chemie MeSH
- virus dengue účinky léků MeSH
- virus zika účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nucleotide prodrugs (ProTides) based on phosphate or phosphonate compounds are potent and successfully marketed antiviral drugs. Although their biological properties are well explored, experimental evidence on the mechanism of their activation pathway is still missing. In this study, we synthesized two ProTide analogues, which can be activated by UV light. Using 31P and 13C NMR spectroscopy with in situ irradiation, we followed the ProTide activation pathway in various solvents, and we detected the first proposed intermediate and the monoamidate product. Furthermore, we used mass spectrometry (MS) coupled with infrared spectroscopy in the gas phase to detect and to characterize the elusive cyclic pentavalent phosphorane and cyclic acyl phosphoramidate intermediates. Our combined NMR and MS data provided the first experimental evidence of the cyclic intermediates in the activation pathway of ProTide prodrugs.
The aminopyrimidine structural motif can be found in diverse biologically active compounds. This study aimed to describe the antioxidant activity of a series of di- and tri-substituted 5-aminopyrimidines using in vitro (TEAC, LPO) and cell-based assays. 2,4,6-trisubstituted 5-aminopyrimidines displayed the highest activity in the TEAC and LPO assays whereas compounds with protected 5-aminogroup were active in the cellular assay. This is most likely because of their better membrane permeability and intracellular metabolic activation. In summary, we have identified the antioxidant activity of a series of substituted 5-aminopyrimidines and their potential prodrugs which may have implications in the treatment of oxidative stress-related diseases.
- MeSH
- aminy chemická syntéza chemie farmakologie MeSH
- antioxidancia chemická syntéza chemie farmakologie MeSH
- buňky Hep G2 MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- oxidace-redukce MeSH
- peroxidace lipidů účinky léků MeSH
- pyrimidiny chemická syntéza chemie farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The oxidation reactions of 5-aminopyrimidine derivatives in dimethyl sulphoxide (DMSO) were studied. The DMSO solutions of the studied compounds became deeply coloured within a few hours or days. The oxidation products can undergo further condensation reactions with the starting pyrimidines to yield bipyrimidines and/or pyrimidopteridines. The reaction mechanism of the oxidation-condensation reaction was also supported by reactions of the 5-aminopyrimidines with alloxan (2,4,5,6-tetraoxopyrimidine). DMSO is often used as the solvent in in vitro tests of biological activities, but it is also an oxidising agent and may react with solute molecules and significantly affect the quality of the generated biochemical data.
