ORCID Profile
0000-0002-4768-3422
Current Organisation
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CC06928K
Abstract: A robust method based on NMR traceable cyclic intermediates clearly distinguished self-immolation from other cargo-release processes.
Publisher: Wiley
Date: 20-07-2020
Publisher: Elsevier BV
Date: 04-2023
Publisher: Czech Chemical Society
Date: 15-07-2022
DOI: 10.54779/CHL20220395
Abstract: NMR spectroscopy is the key analytical method for determination of chemical structure and investigation of physico-chemical properties, such as non-covalent interactions, tautomeric equilibria or polymorphism. In this work, selected ex les of using advanced NMR methods in structural analysis are discussed. (1) NMR spectroscopy with in situ irradiation useful to monitor photochemical processes, (2) 31P NMR spectroscopy for reaction monitoring and probing stereochemistry and (3) solid-state NMR spectroscopy to investigate polymorphism.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.CHROMA.2018.07.083
Abstract: For the first time, capillary electrophoresis has been successfully employed for the fast and highly efficient separations of a novel type of stereoisomers - planar rotamers (planamers) of four newly synthesized 5-nitrosopyrimidine derivatives. These derivatives can form two rotamers differing in the orientation of nitroso group due to strong intramolecular hydrogen bonds. Partial separation of rotamers of two 5-nitrosopyrimidines was achieved in alkaline 50 mM sodium tetraborate, pH 9.3, and in acidic 18.5/42 mM Tris hosphate, pH 2.3, background electrolytes (BGEs) free of stereoselectors. To improve the separation of these rotamers and to attain the baseline or better separation of rotamers of other two 5-nitrosopyrimidines, various BGEs and different cyclodextrins-based stereoselectors were tested. The most effective, i.e. the fastest and baseline or better separations of rotamers of all analyzed 5-nitrosopyrimidines were achieved within a short time, 3.7-9.3 min, in the above alkaline or acidic BGEs using β-cyclodextrin (β-CD) or carboxymethyl-β-CD as stereoselectors. Moreover, since the experiments with β-CD resulted in good separations of rotamers of all the investigated 5-nitrosopyrimidines, the apparent binding constants of their complexes with this selector were determined from the dependence of their effective mobilities on the β-CD concentration in the BGEs. The examined complexes were found to be relatively weak, with the apparent binding constants in the range 11.3-153.0 L/mol.
Publisher: American Chemical Society (ACS)
Date: 16-04-2020
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.BCP.2011.04.002
Abstract: Acyclic nucleotide analogue PMEG represents promising drug candidate against lymphomas. In the present work we describe the ability of PMEG to induce resistance and we elucidate the mechanisms involved in this process. CCRF-CEM T-lymphoblastic cells resistant to either PMEG or its 6-amino congener PMEDAP were prepared and assayed for the expression of membrane transporters, PMEG and PMEDAP uptake and intracellular metabolism. Genes for guanylate kinase (GUK) and adenylate kinase (AK) isolated from PMEG- and PMEDAP-resistant cells were sequenced and cloned into mammalian expression vectors. PMEG-resistant cells were transfected with GUK vectors and catalytic activities of GUKs isolated from PMEG-sensitive and resistant cells were compared. PMEG phosphorylation to PMEG mono- and diphosphate was completely impaired in resistant cells. GUK obtained from PMEG-resistant cells revealed two point mutations S(35)N V(168)F that significantly suppressed its catalytic activity. Transfection of resistant cells with wtGUK led to the recovery of phosphorylating activity as well as sensitivity towards PMEG cytotoxicity. No differences in PMEG uptake have been found between sensitive and resistant cells. In contrast to GUK no changes in primary sequence of AK isolated from PMEDAP resistant cells were identified. Therefore, resistance induced by PMEDAP appears to be conferred by other mechanisms. In conclusion, we have identified GUK as the sole molecular target for the development of acquired resistance to the cytotoxic nucleotide PMEG. Therefore, PMEG is unlikely to cause cross-resistance in combination therapeutic protocols with most other commonly used anticancer drugs.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2CP02325C
Abstract: Unsymmetrical benzothiazole based dithienylethenes represent P-type photoswitches with high thermal stability, efficient photocyclization, good resistance to photodegradation and non-destructive readout possibility of coded information using vibrational spectroscopy.
Publisher: Wiley
Date: 20-07-2020
Publisher: Wiley
Date: 26-02-2012
DOI: 10.1002/MRC.2864
Abstract: We measured the (1)H, (13)C and (15)N chemical shifts for a series of purine derivatives bearing a norbornane substituent in position 9 and various substituents in position 6. The experimental data were complemented with density functional theory (DFT) calculations. The comparison of the calculated and experimental chemical shifts provided us with information about the tautomer and conformational equilibria of the studied compounds.
Publisher: American Chemical Society (ACS)
Date: 27-04-2018
Abstract: The photoswitching behavior of 5-phenylazopyrimidines was investigated by optical methods and NMR spectroscopy with in situ irradiation sustained by mathematical modeling and DFT calculations. Irradiation of various compounds with electron-donating groups on the pyrimidine ring and substituents with electron-withdrawing as well as electron-donating substituent in the para-position of the phenyl ring were examined. All compounds could be successfully converted to the cis isomer this isomerization and the subsequent thermal fading were studied. Switching cycles can be repeated without signs of photodegradation for most of the compounds, which makes them adept to molecular photoswitches. Interestingly, the chloro and cyano derivatives can be switched without UV light, which makes them vis(π → π*)-vis(n → π*) photoswitches. Surprisingly equal trans-to- cis photoisomerization quantum yields for π → π* and n → π* excitation indicate the blocking of the inversion pathway following π → π* excitation. In contrast to that, DFT computations suggest the inversion mechanism for the reverse thermal cis-to- trans isomerization of 5-phenylazopyrimidines.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4CC06978A
Abstract: Unique isolation of pairs of planar rotamers, planamers, as chemical species differing only in nitroso group orientation, separable through the presence of a single intramolecular hydrogen bond, is reported.
Publisher: American Chemical Society (ACS)
Date: 21-01-2022
DOI: 10.1021/ACS.BIOCONJCHEM.1C00536
Abstract: Preexisting serum albumin-polymer bioconjugates have been formed either through covalent conjugation or supramolecular interactions. However, the viability of producing a bioconjugate where both covalent conjugation and supramolecular interactions have been adopted is yet to be explored. In this work, the noncovalent interaction of two polymers bearing fatty acid-based end-functionalities were compared and the superior binder was carried forward for testing with serum albumin that possessed a polymer conjugated to its Cys34 residue. The studies demonstrated that an albumin-polymer bioconjugate equipped with polymers via both covalent and supramolecular interactions can be successfully achieved.
Publisher: Wiley
Date: 04-12-2017
Abstract: NMR spectroscopy with in situ irradiation uncovered unique photoswitchable intramolecular hydrogen bonds (IMHBs) in 5-phenylazopyrimidines with two hydrogen bond donors. These compounds form two stable rotamers, each with one IMHB, and the rotamer ratio changes reversibly upon UV or visible light irradiation. Strong substituent dependence of photoinduced structural changes was observed using suitable substituents, orthogonal photoswitching can be achieved. For ex le, whereas UV irradiation caused switching between the two rotamers of the trans isomer of a compound with electron-donating methoxy substituent, visible light enabled to obtain the cis photoisomer. No cis isomer was detected for compounds with electro-neutral or electron-accepting substituents, but photoswitching between the two trans isomers was observed. On the other hand, compounds without hydrogen-bond donors or with one donor only formed stable cis isomers. A mechanism of the photoswitching was proposed by DFT computations.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2GC35547G
Publisher: Wiley
Date: 25-08-2015
Abstract: Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG.
Publisher: American Chemical Society (ACS)
Date: 07-04-2016
Abstract: The effect of push-pull interactions in a series of variously substituted 5-nitrosopyrimidines on the strength of intramolecular hydrogen bonds, the height of rotational barriers around formally single bonds, UV-vis spectra and electrochemical behavior is explored. Intramolecular charge transfer (ICT) leads to a shift of electron density from electron-donating substituents, which is readily observable by NMR spectroscopy. The 5-nitroso group is able to form strong intramolecular hydrogen bonds with neighboring amino substituents. As a result, two rotamers with reversed orientation of the 5-nitroso group are observed for compounds with two different hydrogen-bond donors in neighboring positions. The barriers of interconversion between the two rotamers are strongly influenced by ICT, whereas the ratio of such rotamers depends primarily on the character of the hydrogen-bond donors. The ICT also significantly affects the position of UV-vis absorption maxima, which can be tuned in a broad range of 100 nm by the selection of appropriate substituents. Finally, ICT influences oxidation potential of the 5-nitrosopyrimidines and the stability of the resulting nitroso radical cations, the structures of which are determined by EPR spectroscopy.
Publisher: American Chemical Society (ACS)
Date: 11-06-2013
DOI: 10.1021/JP404382F
Abstract: Depending on crystallization conditions, many organic compounds can form crystals of different structure. Their proper characterization is important, for ex le, in the pharmaceutical industry. While the X-ray diffractometry established as a standard method, alternative techniques are desirable for broader application flexibility and economic reasons. In the present study, Raman spectroscopy combined with the density functional calculations is suggested as a complementary method to the X-ray and other higher resolution techniques. The potential to discriminate structural differences in polymorphic crystalline forms is documented on three model compounds of industrial importance. Methacrylamide, piracetam, and 2-thiobarbituric acid were crystallized under various conditions, and their Raman spectra were recorded using 532 and 1064 nm laser excitations. X-ray diffractometry and nuclear magnetic resonance spectroscopy were used as complementary techniques to verify s le composition and structure. To interpret the observed differences in Raman frequencies and intensities, three computational strategies were explored based on single molecule, a cluster model, and a plane-wave periodic boundary conditions calculation. The single-molecule modeling was found inadequate, whereas the plane-wave approach provides the most realistic spectra. For all compounds, the differences in the Raman spectra of polymorphic forms could be unambiguously assigned to the simulations. The modeling revealed that the spectral differences were caused by the molecular structure itself as well as by crystal packing. The relative importance of these factors significantly varied across the investigated s les. Owing to its simplicity, Raman spectroscopy appears to be a promising technique capable of reliable discriminating between organic crystal polymorphic states.
Publisher: American Chemical Society (ACS)
Date: 10-07-2019
Abstract: Understanding the nature of the drug-polymer interactions in micellar drug delivery systems and what happens with the drug and the polymer once the complex has formed is essential for the rational design of the polymeric matrices suitable for a particular drug. In this work, glycopolymeric vesicles-a block copolymer, poly(1-
Publisher: SAGE Publications
Date: 2018
Abstract: While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC 50 = 2.6 µM, TK + Oka strain) and HCMV (EC 50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC 50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK – VZV 07–1 strain with EC 50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.
Publisher: Wiley
Date: 20-07-2020
Publisher: American Chemical Society (ACS)
Date: 27-09-2013
DOI: 10.1021/JO401441Z
Abstract: The formation of strong intramolecular hydrogen bonds was observed in a series of 2-amino-5-nitrosopyrimidines with alkylamino and arylamino substituents at positions 4 and 6. Mixtures of two rotamers differing in the orientation of the nitroso group were observed in the NMR spectra of the compounds where two distinct intramolecular hydrogen bonds could be formed. The ratio of the two rotamers depends strongly on the character of the substituents at positions 4 and 6 and can be finely tuned over a broad range of conformation ratios. The experimental results were supported by DFT calculations, which also made it possible to explain the apparent contradiction in the experimental dependence of the rotamer ratio on the Hammett constants for the arylamino substituents. The UV/vis spectra of the compounds also significantly depend on the nature of the substituents however, the orientation of the nitroso group does not have any influence on the position of the absorption bands in the spectra.
Publisher: Elsevier BV
Date: 03-2022
Publisher: American Chemical Society (ACS)
Date: 19-12-2020
Publisher: Wiley
Date: 07-08-2021
Abstract: Invited for the cover of this issue are Eliška Procházková, Ondřej Baszczyňski, and colleagues at IOCB (Prague) and Charles University (Prague). The image depicts phosphorus‐based, double‐cargo, self‐immolative linkers capable of releasing both cargos sequentially after activation by light. Read the full text of the article at 10.1002/chem.202101805 .
Publisher: MDPI AG
Date: 25-08-2021
DOI: 10.3390/MOLECULES26175160
Abstract: Amine-containing drugs often show poor pharmacological properties, but these disadvantages can be overcome by using a prodrug approach involving self-immolative linkers. Accordingly, we designed l-lactate linkers as ideal candidates for amine delivery. Furthermore, we designed linkers bearing two different cargos (aniline and phenol) for preferential amine cargo release within 15 min. Since the linkers carrying secondary amine cargo showed high stability at physiological pH, we used our strategy to prepare phosphate-based prodrugs of the antibiotic Ciprofloxacin. Therefore, our study will facilitate the rational design of new and more effective drug delivery systems for amine-containing drugs.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.BMCL.2012.08.065
Abstract: 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.
Publisher: Wiley
Date: 23-11-2016
Abstract: We report on a detailed NMR spectroscopic study of the catalyst-substrate interaction of a highly enantioselective oligopeptide catalyst that is used for the kinetic resolution of trans-cycloalkane-1,2-diols via monoacylation. The extraordinary selectivity has been rationalized by molecular dynamics as well as density functional theory (DFT) computations. Herein we describe the conformational analysis of the organocatalyst studied by a combination of nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC)-based methods that resulted in an ensemble of four final conformers. To corroborate the proposed mechanism, we also investigated the catalyst in mixtures with both trans-cyclohexane-1,2-diol enantiomers separately, using advanced NMR methods such as T
Publisher: Wiley
Date: 29-09-2022
Abstract: Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ′ efficacy and safety no longer justify its use as a first‐line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine‐modified KTZ derivatives and we evaluated their in vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24 times more potent against Aspergillus flavus and 8 times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100 μM. Derivative 6 had 9‐ and 7‐fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC 50 values. Combined, our findings will foster further research of piperazine‐modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.
Publisher: Informa UK Limited
Date: 28-11-2011
DOI: 10.3109/10715762.2011.638292
Abstract: The aminopyrimidine structural motif can be found in erse 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.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8OB00019K
Abstract: Synthesis and biological evaluation of tRNA analogues containing a terminal ribose locked in the South conformation.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8OB02870B
Abstract: A combination of NMR and IRPD spectroscopy confirmed the existence of predicted cyclic phosphorus intermediates involved in ProTide prodrugs activation.
Publisher: Wiley
Date: 20-07-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5CC05199A
Abstract: Nuclear quantum effects are shown to be important for resonance stabilisation of intramolecular hydrogen bonds.
Publisher: American Chemical Society (ACS)
Date: 08-09-2017
Abstract: Intramolecular hydrogen bonds (IMHBs) in 5-azopyrimidines are investigated by NMR spectroscopy and DFT computations that involve nuclear quantum effects. A series of substituted 5-phenylazopyrimidines with one or two hydrogen bond donors able to form IMHBs with the azo group is prepared by azo coupling. The barrier of interconversion between two rotamers of the compounds with two possible IMHBs is determined by variable temperature NMR spectroscopy and it is demonstrated that the barrier is significantly affected by intramolecular charge transfer. Through-hydrogen-bond scalar coupling is investigated in
Publisher: Wiley
Date: 29-03-2012
DOI: 10.1002/MRC.3806
Abstract: Four- and five-bond heteronuclear J-couplings between the hydrogen H-8 and carbons C-6 and C-2 in a series of 7- and 9-benzyl substituted purine derivaties with variuous substituents in positions 2 and 6 were studied by coupled (13) C NMR and H,C-HMBC experiments and by DFT calculations. We have found that for some of the derivatives, the five-bond coupling H8-C2 is higher than the four-bond H8-C6 coupling, which is also evidenced by a stronger crosspeak in the HMBC. This finding contradicts the generally accepted opinion that only strong three-bond crosspeaks and one weak four-bond H8-C6 crosspeak can be observed in the HMBC spectra of purine derivatives. The misinterpretation of HMBC spectra may lead to an incorrect determination of the purine derivatives' structure.
Location: Czechia
Location: Germany
No related grants have been discovered for Eliska Prochazkova.