Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors.

Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen-Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 µM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors.

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.

Synthesis, Biological Evaluation and Docking Studies of Benzoxazoles Derived from Thymoquinone.

Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (¹H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R ß) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.

Evaluation of the adsorption potential of eco-friendly activated carbon prepared from cherry kernels for the removal of Pb2+, Cd2+ and Ni2+ from aqueous wastes.

Development, characterization and evaluation of the efficiency of cost-effective medium for the removal of Pb2+, Cd2+ and Ni2+ from aqueous systems, as a novel, eco-friendly solution for wastewater remediation were done. The precursors for low-cost adsorbent were lignocellulosic raw materials (sweet/sour cherry kernels), as industrial byproducts and components of organic solid waste. Activated carbon synthesis was carried out by thermochemical conversion (H3PO4, 500 °C) in the complete absence of inert atmosphere. Characterization of the activated carbon was performed by elemental analysis, FTIR, SEM, EDX and BET. BET surface area corresponds to 657.1 m2 g-1. The evaluation also included the influence of pH, contact time, solute concentration and adsorbent dose on the separation efficiency in the batch operational mode. The equilibrium and kinetic studies of adsorption were done. The maximum adsorption capacity of the activated carbon for Cd2+ ions was calculated from the Langmuir isotherm and found to be 198.7 mg g-1. Adsorption of Pb2+ and Ni2+ were better suitable to Freundlich model with the maximum adsorption capacity of 180.3 mg g-1 and 76.27 mg g-1, respectively. The results indicate that the pseudo-second-order model best describes adsorption kinetic data. Based on desorption study results, activated carbon was successfully regenerated with HNO3 for 3 cycles. In order to provide the results for basic cost-effective analysis, competing ion-effects in a real sample have been evaluated.

Isolation, characterization, and in vitro cytotoxicity of new sesquiterpenoids from Achillea clavennae.

Further phytochemical investigation of the aerial parts of Achillea clavennae has resulted in the isolation of three new sesquiterpene lactones: two highly oxygenated germacranolides (1, 2) and the iso-seco-guaianolide 9(R)-acetoxy-3-O-methyl-iso-seco-tanapartholide (3). Eight known compounds were also found, of which 9α-acetoxycanin (5), sintenin (6), and oleanolic acid (7) were detected for the first time. The structures of the isolated compounds were elucidated by combined spectroscopic methods (1D and 2D NMR, HRESIMS, CIMS, and FTIR). While the predominant metabolite germacranolide sintenin (6) was not cytotoxic, the new iso-seco-guaianolide (3) displayed cytotoxicity comparable to that of cisplatin and the lactone apressin (4), inducing partly apoptotic death in human U251 and rat C6 glioma cell lines.

Diarylheptanoids from green alder bark and their potential for DNA protection.

Nine diarylheptanoids, 1-9, catechin (11), and a phenolic glucoside, 10, were isolated from the bark of green alder (Alnus viridis). Four of the isolated compounds, i.e., 2, 5, 8, 10, are new. The structures of 1-11 were determined on the basis of spectroscopic data. All isolated compounds were evaluated for their in vitro protective effects on chromosome aberrations in peripheral human lymphocytes using cytokinesis-block micronucleus (CBMN) assay. Almost all of them exerted a pronounced effect of decreasing DNA damage of human lymphocytes, acting stronger than the known synthetic protector amifostine.

Diarylheptanoids from Alnus glutinosa bark and their chemoprotective effect on human lymphocytes DNA.

A study of secondary metabolites from the bark of Alnus glutinosa led to the isolation of fourteen diarylheptanoids: oregonin (1), platyphylloside (2), rubranoside A (3), rubranoside B (4), hirsutanonol (5), hirsutenone (6), hirsutanonol-5-O-ß-D-glucopyranoside (7), platyphyllonol-5-O-ß-D-xylopyranoside (8), aceroside VII (9), alnuside A (10), alnuside B (11), 1,7-bis-(3,4-dihydoxyphenyl)-5-hydroxy-heptane-3-O-ß-D-xylopyranoside (12), (5S)-1-(4-hydroxyphenyl)-7-(3,4-dihydroxyphenyl)-5-O-ß-D-glucopyranosyl-heptan-3-one (13), and (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-O-ß-D-[6-(3,4-dimethoxycinnamoylglucopyranosyl)]-heptan-3-one (14). All of the diarylheptanoids, except 1 and 5, were found in A. glutinosa for the first time, while 13 and 14 were new compounds. The structures were determined by spectroscopic techniques: 1D and 2D NMR, HR-ESI-MS, FTIR, UV, and CD. All isolated compounds were analyzed for an in vitro protective effect on chromosome aberrations in peripheral human lymphocytes using the cytokinesis-block micronucleus assay. The majority of them, including the new compounds 13 and 14, exerted a pronounced effect in decreasing DNA damage in human lymphocytes. Diarylheptanoids 1, 2, 5, 13, and 14 at a concentration of 1 µg/mL decreased the frequency of micronuclei by 52.8 %, 43.8 %, 63.6 %, 44.4 %, and 56.0 %, respectively, exerting a much stronger effect than the synthetic protector amifostine (17.2 %, c = 1 µg/mL).

Pyrrolizidine alkaloids and fatty acids from the endemic plant species Rindera umbellata and the effect of lindelofine-N-oxide on tubulin polymerization.

The examination of the aerial parts, roots, and seeds of the endemic plant Rindera umbellata is reported in this paper for the first time. Phytochemical investigation of R. umbellata led to the isolation and characterization of ten pyrrolizidine alkaloids and eleven fatty acids in the form of triglycerides. Pyrrolizidine alkaloids 1-9 were found in the aerial parts, 7 and 8 in the roots, and 6-10, together with eleven fatty acids, in the seeds of this plant species. The structures of compounds 1-10 were established based on spectroscopic studies (¹H- and ¹³C-NMR, 2D NMR, IR and CI-MS). After trans-esterification, methyl esters of the fatty acids were analyzed using GC-MS. The effect of lindelofine-N-oxide (7) on tubulin polymerization was determined.

The significance of applying different factors for the evaluation of sediment contamination by toxic elements and estimation of the ecological risk.

The optimized three-step sequential extraction procedure for the fractionation of micro- and macroelements, was conducted to determine fractional characteristics of PTEs (potentially toxic elements) in surface sediments of rivers in the Vlasina watershed. The sequential extraction results, which enable the evaluation of mobility of the studied elements, have indicated that Zn, Ni, Cu, Cr, and As can be considered slightly mobile, whereas Pb, Mn, Cd, and Co were regarded as possibly mobile elements. Lead was dominantly bounded (specifically adsorbed or co-precipitated) to iron and manganese oxides (up to 80%) and may be released by reduction. Since the content of the exchangeable fraction (F1) is an indicator for anthropogenic impact on the aquatic environment, a low percentage (0-8%) of studied toxic elements in this fraction indicated that these elements have lithogenic origin in most sampling locations in the area of study. Except for Pb, the substantial positive correlations between Al and other elements showed that studied elements came primarily from terrigenous sources. Although the values obtained for the risk assessment code (RAC) indicated a slightly increased mobility of some elements (up to 22.44%), the values of the modified risk assessment code (mRAC), which include toxic effects on the environment, showed there is no danger of pollution by studied elements (all values were < 1%). Our recommendation is to use mRAC instead of RAC in ecochemical studies and assessment of the degree of sediment and soil pollution, because mRAC includes toxic effects of elements. Based on ATI values, river sediments show no toxic to a low toxic degree. Even though obtained results indicate that there was no considerable risk for river water contamination, the ecological risk for Fe and Pb should be monitored in the future.

Metabolomic Profiling of Bipolar Disorder by 1H-NMR in Serbian Patients.

Bipolar disorder (BD) is a brain disorder that causes changes in a person's mood, energy, and ability to function. It has a prevalence of 60 million people worldwide, and it is among the top 20 diseases with the highest global burden. The complexity of this disease, including diverse genetic, environmental, and biochemical factors, and diagnoses based on the subjective recognition of symptoms without any clinical test of biomarker identification create significant difficulties in understanding and diagnosing BD. A 1H-NMR-based metabolomic study applying chemometrics of serum samples of Serbian patients with BD (33) and healthy controls (39) was explored, providing the identification of 22 metabolites for this disease. A biomarker set including threonine, aspartate, gamma-aminobutyric acid, 2-hydroxybutyric acid, serine, and mannose was established for the first time in BD serum samples by an NMR-based metabolomics study. Six identified metabolites (3-hydroxybutyric acid, arginine, lysine, tyrosine, phenylalanine, and glycerol) are in agreement with the previously determined NMR-based sets of serum biomarkers in Brazilian and/or Chinese patient samples. The same established metabolites (lactate, alanine, valine, leucine, isoleucine, glutamine, glutamate, glucose, and choline) in three different ethnic and geographic origins (Serbia, Brazil, and China) might have a crucial role in the realization of a universal set of NMR biomarkers for BD.

Pyrazolone-type compounds: synthesis and in silico assessment of antiviral potential against key viral proteins of SARS-CoV-2.

Coronavirus outbreak is still a major public health concern. The high mutation ability of SARS-CoV-2 periodically delivers more transmissible and dangerous variants. Hence, the necessity for an efficient and inexpensive antiviral agent is urgent. In this work, pyrazolone-type compounds were synthesised, characterised using spectroscopic methods and theoretical tools, and evaluated in silico against proteins of SARS-CoV-2 responsible for host cell entry and reproduction processes, i.e., spike protein (S), Mpro, and PLpro. Five of twenty compounds are newly synthesised. In addition, the crystal structure of a pyrazolone derivative bearing a vanillin moiety is determined. The obtained in silico results indicate a more favourable binding affinity of pyrazolone analogues towards Mpro, and PLpro in comparison to drugs lopinavir, remdesivir, chloroquine, and favipiravir, while in the case of S protein only lopinavir exerted higher binding affinity. Also, the investigations were performed on ACE2 and the spike RBD-ACE2 complex. The obtained results for these proteins suggest that selected compounds could express antiviral properties by blocking the binding to the host cell and viral spreading, also. Moreover, several derivatives expressed multitarget antiviral action, blocking both binding and reproduction processes. Additionally, in silico ADME/T calculations predicted favourable features of the synthesised compounds, i.e., drug-likeness, oral bioavailability, as well as good pharmacokinetic parameters related to absorption, metabolism, and toxicity. The obtained results imply the great potential of synthesised pyrazolones as multitarget agents against SARS-CoV-2 and represent a valuable background for further in vitro investigations.

NMR Metabolomics in Serum Fingerprinting of Schizophrenia Patients in a Serbian Cohort.

Schizophrenia is a widespread mental disorder that leads to significant functional impairments and premature death. The state of the art indicates gaps in the understanding and diagnosis of this disease, but also the need for personalized and precise approaches to patients through customized medical treatment and reliable monitoring of treatment response. In order to fulfill existing gaps, the establishment of a universal set of disorder biomarkers is a necessary step. Metabolomic investigations of serum samples of Serbian patients with schizophrenia (51) and healthy controls (39), based on NMR analyses associated with chemometrics, led to the identification of 26 metabolites/biomarkers for this disorder. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models with prediction accuracies of 0.9718 and higher were accomplished during chemometric analysis. The established biomarker set includes aspartate/aspartic acid, lysine, 2-hydroxybutyric acid, and acylglycerols, which are identified for the first time in schizophrenia serum samples by NMR experiments. The other 22 identified metabolites in the Serbian samples are in accordance with the previously established NMR-based serum biomarker sets of Brazilian and/or Chinese patient samples. Thirteen metabolites (lactate/lactic acid, threonine, leucine, isoleucine, valine, glutamine, asparagine, alanine, gamma-aminobutyric acid, choline, glucose, glycine and tyrosine) that are common for three different ethnic and geographic origins (Serbia, Brazil and China) could be a good start point for the setup of a universal NMR serum biomarker set for schizophrenia.

Antiproliferative activity and QSAR studies of a series of new 4-aminomethylidene derivatives of some pyrazol-5-ones.

Twenty five 4-aminomethylidene derivatives obtained from 3-phenyl-2-pyrazolin-5-one and 1,3-diphenyl-2-pyrazolin-5-one were synthesized and tested for their antiproliferative activity against human breast cancer MDA-MB-361 and MDA-MB-453 cell lines. The compounds derived from 1,3-diphenyl-2-pyrazolin-5-one exhibited the most remarkable activity in the treatment of both cell lines. In vitro antiproliferative activities were accompanied by an important apoptotic fraction of both cell lines; also, compounds inhibited key endothelial cell functions implicated in invasion and angiogenesis. QSAR methods were performed in order to analyze the influence of structural features of the compounds investigated on the antiproliferative potential on MDA-MB-361 and MDA-MB-453 cancer cells. One-parameter heuristic analysis was performed and different whole molecule and fragmental descriptors were considered for rationalization of mechanism of interaction of these compounds with active place of hypothetical target included in tumorigenesis.

Study of the Synergetic Effect of Co-Pyrolysis of Lignite and High-Density Polyethylene Aiming to Improve Utilization of Low-Rank Coal.

The mutual impact of low-quality lignite and high-density polyethylene (HDPE) during open system pyrolysis was investigated, aiming to improve utilization of lignite with simultaneous treatment of HDPE waste. Pyrolysis of lignite, HDPE, and their mixture (mass ratio, 1:1) was performed at temperatures 400, 450, 500, 550, and 600 °C. Initial substrates and pyrolysis products were characterized by thermogravimetric analysis (TGA), gas chromatography-mass spectrometry (GC-MS), specific carbon isotope analysis of individual hydrocarbons (δ13C), Rock-Eval pyrolysis, and elemental analysis. The positive synergetic effect during co-pyrolysis of lignite/HDPE mixture was observed at temperatures ≥450 °C, with the greatest being at 500 °C. The highest yield of liquid co-pyrolysis products with a similar composition to that of crude oils is also noticed at 500 °C. The yields of liquid and gaseous products and quality of pyrolytic products obtained by co-pyrolysis of lignite/HDPE mixture are notably improved compared with pyrolysis of lignite alone. On the other hand, data obtained from pyrolysis of HDPE alone indicate that it cannot be concurrent to well-developed catalytic thermal processes for polymer recycling. However, concerning the huge amount of produced HDPE, at least part of this plastic material can be reused for advanced thermal treatment of lignite, particularly in countries where this low-rank coal represents the main source of energy.

Chitosan Nanoparticles Functionalized Viscose Fabrics as Potentially Durable Antibacterial Medical Textiles.

This research proposed two pretreatments of viscose fabrics: oxidation with 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO) and coating with TEMPO-oxidized cellulose nanofibrils (TOCN), to introduce functional groups (COOH and CHO) suitable for irreversible binding of chitosan nanoparticles without and with embedded zinc (NCS and NCS + Zn, respectively) and consequently achieving washing durable antibacterial properties of the chitosan nanoparticles functionalized fabrics. The characterizations of pretreated and chitosan nanoparticles functionalized fabrics were performed by FTIR and XPS spectroscopy, elemental analysis, inductively coupled plasma optical emission spectrometry, zeta potential measurements, scanning electron microscopy, determination of COOH and CHO groups content, and antimicrobial activity under dynamic contact conditions. Influence of pretreatments on NCS and NCS + Zn adsorption, chemical, electrokinetic, and antibacterial properties as well as morphology, and washing durability of NCS and NCS + Zn functionalized fabrics were studied and compared. Washing durability was evaluated through changes in the chitosan and zinc content, zeta potential, and antibacterial activity after 1, 3, and 5 washing cycles. Pretreatments improved washing durability of antibacterial properties of chitosan nanoparticles functionalized fabrics. The NCS and NCS + Zn functionalized pretreated fabrics preserved antibacterial activity against S. aureus after five washing cycles, while antibacterial activity against E. coli was preserved only after one washing cycle in the case NCS + Zn functionalized pretreated viscose fabrics.

Composition, Antioxidant Potential, and Antimicrobial Activity of Helichrysum plicatum DC. Various Extracts.

Helichrysum plicatum DC. is widely used in folk medicine in treating a variety of health disorders. The aim of this study was to examine the influence of different extraction solvents on the chemical composition, antioxidant potential, and antimicrobial activities of H. plicatum. Aerial parts were separately extracted with ethanol, dichloromethane, and sunflower oil. The oil extract (OE) was re-extracted with acetonitrile. A total of 142 compounds were tentatively identified in ethanolic (EE), dichloromethane (DCME), and acetonitrile (ACNE) extracts using HPLC-DAD/ESI-ToF-MS. The dominant compound class in all extracts were α-pyrones, alongside flavonoids in EE, terpenoids in DCME and ACNE, and phloroglucinols in DCME. The antioxidant potential of the extracts was assessed by the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assay. EE and DCME possessed the most potent radical scavenging capacity. Antimicrobial activity was investigated on eight bacterial, two yeast, and one fungal species. All extracts exhibited high antifungal and notable antibacterial activities compared to control substances, with DCME being the most potent. DCME exhibited stronger antimicrobial activity against P. aeruginosa than the standard chloramphenicol.

Chemical Composition, Total Phenols and Flavonoids Contents and Antioxidant Activity as Nutritive Potential of Roasted Hazelnut Skins (Corylus avellana L.).

The present study evaluates natural composition of Serbian roasted hazelnut skins (HS) with potential role in application as functional nutrient of various food products. Total phenols (TPC) and flavonoids contents (TFC) in HS extracts obtained with different ethanol concentrations (10%-I, 50%-II and 96%-III) and their antioxidant activities were investigated. The highest total phenols content (706.0 ± 9.7 mgGAE/gextract) was observed in 96% ethanol HS extract. Ethanol HS extracts showed very high antioxidant activity with effective concentrations (EC50) ranged between 0.052 and 0.066 mg/mL. The phenol and flavonoid content of roasted HS extracts I-III was determined by HPLC-ESI-MS/MS analyses. Contents of lipids, proteins, carbohydrates, metals, and C, H, N, S elements in roasted HS were also determined. Relatively high C/N, C/P and C/N/P ratios, rich metal contents and fatty acids composition indicated that hazelnut skin might be a good candidate for use as either human or fungal functional nutrient. In addition, possible application of phenolic HS extracts as UV booster was studied by recording UV spectra (220-440 nm) of 10 mg/L of HS extracts I-III combined with 10 mg/L of chemical sunscreen agent benzophenone-3 and in vitro sun protection factor (SPF) was calculated.

Influence of Different Pretreatments on the Antibacterial Properties of Chitosan Functionalized Viscose Fabric: TEMPO Oxidation and Coating with TEMPO Oxidized Cellulose Nanofibrils.

The main objective of this study was to obtain chitosan functionalized viscose fabric with improved antibacterial properties and washing durability. In this regard carboxyl and aldehyde groups, as binding points for irreversible chitosan attachment into/onto viscose fabric, were introduced by two different pretreatments: 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO) oxidation and coating with TEMPO oxidized cellulose nanofibrils (TOCN). The Fourier transform infrared spectroscopy, elemental analysis, zeta potential measurements, scanning electron microscopy, breaking strength and antibacterial testing were used to evaluate the influence of these pretreatments on chitosan binding, but also on chemical, electrokinetic, morphological, mechanical and antibacterial properties of pretreated and chitosan functionalized viscose fabrics. Washing durability of chitosan functionalized viscose was monitored through changes in the chitosan content, electrokinetic and antibacterial properties after multiple washing. TOCN coating improves mechanical properties of fabric, while TEMPO oxidation deteriorates them. The results show that both pretreatments improve chitosan adsorption and thus antibacterial properties, which are highly durable to washing. After five washings, the chitosan functionalized pretreated viscose fabrics preserve their antibacterial activity against Staphylococcus aureus, while antibacterial activity against Escherichia coli was lost. TOCN coated and chitosan functionalized viscose fabric is a high value-added product with simultaneously improved antibacterial and mechanical properties, which may find application as medical textiles.

New aurone epoxide and auronolignan from the heartwood of Cotinus coggygria Scop.

New aurone epoxide, 2,10-oxy-10-methoxysulfuretin (14), and new auronolignan (15), named cotinignan A, were isolated by silica gel column and semipreparative HPLC chromatography from the methylene chloride/methanol extract of Cotinus coggygria Scop. heartwood. In addition, thirteen known secondary metabolites namely sulfuretin, 2,3-trans-fustin, fisetin, butin, butein, taxifolin, eriodictyol, 3',5,5',7-tetrahydroxyflavanone, 3',4',7-trihydroxyflavone, 3-O-methyl-2,3-trans-fustin, 3-O-galloyl-2,3-trans-fustin, ß-resorcylic acid and 3-O-ß-sitosterol glucoside were isolated as well. Their structures were elucidated by 1D and 2D NMR, HR-ESI-MS, IR and UV. Ten out of eleven isolated flavonoids possess 7, 3' and 4' hydroxy groups. These structural features could be considered as chemotaxonomic characteristic of flavonoids from C. coggygria. Cotinignan A (15) represents new subclass of secondary metabolites - auronolignans.

Stereochemistry and conformations of natural 1,2-epoxy-guaianolides based on 1D and 2D NMR data and semiempirical calculations.

From detailed study of 1D and 2D NMR spectra of ten natural 1,2-epoxyguaianolides (bis-1,2:3,4-epoxyguaianolides and guaianolide-1,2-epoxychlorohydrins), we identified general spectral traits helpful for stereochemical assignment of such sesquiterpene lactones. We found that the chemical shifts of certain (1)H and (13)C nuclei are consistently dependent on the configuration of 1,2-epoxy-ring which could be used as a simple rule for establishing this configuration. Then, from 1D and 2D (COSY, NOESY, HMQC, HMBC) NMR data, applying the observed rule, the structure and stereochemistry of two new, diastereomeric guaianolide-1,2-epoxychlorohydrins, isolated from Achillea serbica, are determined. The NMR data, namely, nuclear overhauser enhancement (NOE) correlations, pointed out two conformations of guaianolide's cycloheptane ring. The semiempirical calculations (AM1 and PM3 methods), performed in order to gain additional information regarding conformations, resulted in three geometries of investigated lactones. Even so, the conformations derived from the NMR data agreed well with those calculated by semiempirical methods.