Marine sponges are sessile invertebrates found in moderate, arctic, and tropical regions, serving as a valuable reservoir of bioactive compounds, particularly Pro-rich peptides. Among these, cyclic peptides have attracted significant interest due to their diverse therapeutic properties. One notable example is Stylissatin A (SA), a Pro-rich cyclic peptide reported from the marine sponge Stylissa massa. SA and its analogues have shown promising biological activities, including anti-inflammatory, anticancer, and anti-obesity effects. Despite the vast potential of marine-derived peptides, only a small number have progressed to the pharmaceutical market. Cyclic peptides like SA offer unique opportunities for molecular modifications and total synthesis, enabling the enhancement of potency, improvement of physicochemical properties, and optimization of synthetic yields. This review highlights the synthetic strategies developed for the total synthesis of SA, explores its structural features and related analogues, and discusses their therapeutic potential, underscoring the promise of SA-based scaffolds as novel peptide-based drug candidates.

Overcoming line broadening of labile protons and achieving high-resolution NMR spectra is crucial for the structural and conformational analysis of organic molecules. Recently, Ma et al. (Magn. Reson. Chem. 2024, 62, 198-207) demonstrated the effectiveness of 2,2,2-trifluoroacetic acid (TFA) in sharpening NMR signals for nitrogen-containing compounds which exhibit prototropic tautomerization or conformational isomerism using high molar ratio of [acids]/[solute] similar to 5 to 200. In this commentary, we provide an overview of earlier publications and highlight the extensive applications of TFA in enhancing NMR resolution across a variety of organic functional groups, with the use of very small ratios of [acids]/[solute] similar to 10(-3) to 10(-2). The prospects for the unequivocal structure analysis using labile protons as the starting point will be analyzed.

Base-catalyzed H/D exchange reactions through keto-enol tautomeric equilibrium are a textbook example in mechanistic organic chemistry. The pH effect of H2O catalysis, however, is largely unknown. We report, herein, variable temperature and pD 1H NMR studies of the experimental activation enthalpy , entropy , and Gibbs free energy of H/D exchange reactions of the H-6 and H-8 protons belonging to ring A of the natural product taxifolin. The experimental values range from similar to 25 to 23 kcal mol-1 for pD values of 6.1 to 9.6 and a buffer concentration in the range of 25 to 1000 mM. Differences in values of neutral and anionic taxifolin and phloroglucinol were found to be very small (<= 1.5 kcal mol-1). The experimental data of taxifolin and phloroglucinol were compared with DFT calculations with two up to four H2O molecules explicitly present, which demonstrate a unique catalytic role of H2O of over 35 kcal mol-1. Excellent agreement between and DFT calculated Gibbs free activation energies, , was obtained with the use of three molecules of H2O for the neutral state of phloroglucinol (with the "in-in" configuration of the phenol OH groups) and taxifolin. In the ionic form of phloroglucinol, the mechanistic pathway with two molecules of H2O in the transition state (one of which involves the C 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 O moiety) showed very good agreement with the experimental data. For the anionic form of taxifolin, the mechanistic pathway with three molecules of H2O in the transition state showed excellent agreement with the experimental values. Among the various functionals used, the APFD/6-31+G(d) and B3LYP/6-31+G(d)/GD3BJ resulted in optimum agreement with . The enthalpic term is considerably larger than the entropic term , in agreement with the experimental data. This indicates a dissociative mechanism of the loosely bound activated complex. The present results demonstrate the unique catalytic role of two and/or three molecules of H2O, through keto-enol tautomerization, with minor contribution of base-catalysis, in H/D exchange reactions in aromatic systems.

Phytochemical investigation of the n-hexane-soluble fraction of the aqueous ethanol extract of the aerial parts of Hypericum helianthemoides (Spach) Boiss. (Hypericaceae), furnished four undescribed polycylic polyprenylated benzoylphloroglucinols (PPBPs) 1-4, together with phytyl formate (5) and thirteen previously reported prenylated phloroglucinol derivatives, including yezo'otogirin C (6), hyperibrins A (7) and F (8), hyperibones G (9), J (10), La (11a)/Lb (11b), 7-epi-clusianone a (12a)/7-epi-clusianone b (12b), and hypermongones A (13), C (14), E (15), G (16), H (17), and sampsonione L (18). The structures of 1-4 were established by extensive 1D and 2D NMR spectral analysis as well as HREI-MS. The absolute configurations of the stereogenic carbons in 1 were established by X-ray crystallographic analysis, while the stereochemistry of 2 was assigned by quantum chemical calculation of its 1H and 13C NMR chemical shift values using DP4+ probability analysis. The isolated compounds were assayed for antileishmanial activity on Leishmania tropica and L. major parasites. Compounds 9 and 16 displayed activities against L. tropica, with IC50 values of 17.7 and 31.5 μM, respectively. Moreover, 9 was only active against L. major, with IC50 value of 34.2 μM.

NMR spectroscopy is playing an increasing role in chemistry, biology, material sciences and related disciplines [...]

Detailed DFT studies of 1H and 13C NMR chemical shifts of hydroxy secondary oxidation products of various geometric isomers of conjugated linolenic acids methyl esters are presented. Several low energy conformers were identified for model compounds of the central dienenol OH moiety, which were found to be practically independent on the various functionals and basis sets used. This greatly facilitated the minimization process of the geometric isomers of conjugated linolenic acids methyl esters. Several regularities of the literature experimental H-1 and C-13 chemical shifts were reproduced very accurately with the computational chemical shifts of the Gibbs low energy DFT optimized conformers, after a Boltzmann analysis. 5(C-13) and 5(H-1) of the methine CH- OH group are highly diagnostic for the trans/trans and cis/trans geometric isomerism of the adjacent double bond. 5(C-13) of the -CH2- group adjacent to the terminal double bond of the conjugated system strongly depend on the cis/trans geometric isomerism of this bond and, thus, could be of importance in structural analysis. Ambiguities in the reported literature resonance assignments of olefinic carbons had been resolved. Computational 5(H-1) and 5(C-13) can be utilized for the identification of geometric isomerism and structural and conformational elucidation of hydroxy derivatives of conjugated linoleic acids and their ester derivatives.

The present study aims to develop a green and sustainable process for the effective extraction of phytochemicals bearing antioxidant potency from Colocasia esculenta L. leaves, the by-product of taro cultivation, using beta- cyclodextrin (beta-CD) beta- CD) as a green booster for polyphenol isolation, along with ultrasound irradiation. Process optimization based on response surface methodology demonstrated that the maximum total phenolic content (11.90 mg gallic acid equivalents g-1 - 1 sample), total flavonoid content (4.66 mg catechin equivalents g-1 - 1 sample), and antioxidant activity in terms of 2,2-diphenyl-1-picrylhydrazyl radical inhibition (80.70%) and ferric-reducing antioxidant power (85.39 mu mol trolox equivalents g-1 - 1 sample) could be obtained by ultrasonication of leaves at 59.6 degrees C for 55.4 min using an ethanolic solution (50% v/v) of beta- CD (15 mM) and a solvent-solid ratio of 25.4 mL g-1. - 1 . The extract obtained with beta- CD was significantly enriched in flavonoids and, in particular, flavone derivatives (mainly apigenin and luteolin glucosides). The outcomes of the present study suggest that the proposed extraction procedure can serve as a highly effective and green strategy for the recovery of taro leaf polyphenols opening new horizons in the valorization of underutilized by-products from food and pharmaceutical sector.

Carob leaves have gained attention for their bioactive properties and traditional medicinal uses, including as treatment for diabetes, digestive disorders, and microbial infections. The aim of this study was to explore the phytochemical composition of carob leaf acetone extracts using advanced spectroscopic techniques. The combined use of heteronuclear nuclear magnetic resonance (NMR) experiments with 1D selective nuclear Overhauser effect spectroscopy (NOESY) offers detailed structural insights and enables the direct identification and quantification of key bioactive constituents in carob leaf extract. In particular, the NMR and mass spectrometry techniques revealed the presence of myricitrin as a predominant flavonoid, as well as a variety of glycosylated derivatives of myricetin and quercetin, in acetone extract. Furthermore, siliquapyranone and related gallotannins are essential constituents of the extract. The potent inhibitory effects of the carob leaf extract on Staphylococcus aureus (MIC = 50 μg mL−1) and a-glucosidase enzyme (IC50 = 67.5 ± 2.4 μg mL−1) were also evaluated. Finally, the antibacterial potency of carob leaf constituents were calculated in silico; digalloyl-parasorboside and gallic acid 4-O-glucoside exert a stronger bactericidal activity than the well-known myricitrin and related flavonoids. In summary, our findings provide valuable insights into the bioactive composition and health-promoting properties of carob leaves and highlight their potential for pharmaceutical and nutraceutical applications.

The purpose of this review is to present advances and applications of 33S NMR, which is an underutilized NMR spectroscopy. Experimental NMR aspects in solution, chemical shift tendencies, and quadrupolar relaxation parameters will be briefly summarized. Emphasis will be given to advances and applications in the emerging fields of solid-state and DFT computations of 33S NMR parameters. The majority of the examples were taken from the last twenty years and were selected on the basis of their importance to provide structural, electronic, and dynamic information that is difficult to obtain by other techniques.

OPINION article Front. Pharmacol., 26 January 2023Sec. Experimental Pharmacology and Drug Discovery Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1119419

Natural product-observed NMR methods have considerably expanded the potentialities for in-tube NMR monitoring of complex enzymatic biotransformations and investigation of protein-natural product interactions even in living cells. We review, herein, the significant advantages of ligand-observed in-situ NMR monitoring of enzymatic biotransformations without restoring to laborious and time-consuming chromatographic methods. Emphasis will be given to the potentialities of the use of the NMR bioreactor: (i) to investigate through saturation transfer difference (STD), the capacity of natural products to serve as enzyme substrates, (ii) to monitor multiple biotransformation products of natural products with the use of immobilized enzymes and (iii) to investigate interactions of biotransformed products with protein targets. The use of STD and its variants, transfer effect Noes for PHArmacophore Mapping (INPHARMA) NMR, in conjunction with computational methods, can provide excellent tools in investigating competitive binding modes even in proteins with multiple binding sites. The method has been successfully applied in the study of unsaturated free fatty acids (UFFAs)-serum albumin complexes in which the location and conformational states of UFFAs could not be determined accurately, despite numerous X-ray structural studies, due to conformational averaging. This combined method, thus, may find promising applications in the field of protein-natural product recognition research. The emerging concept of in-cell NMR and recent applications will be discussed since they can provide atomic level insights into natural product-protein interactions in living cells without the need of isotope labelled techniques.

Nature has always been a notable source of bioactive lead compounds and has provided unprecedented opportunities for medicinal chemists to continuously provide drug candidates as new compounds for evaluation. Natural products (NPs) and their derivatives have historically made major contributions to pharmacotherapy, in particular for cancer and infectious diseases. NPs provide intriguing chemical diversity and are considered as being irreplaceable sources of inspiration for new drug discovery and have been validated by their truly enormous contributions in the development of new lead molecules. These secondary metabolites feature diverse chemical structures, and inherently occupy biologically applicable chemical spaces. Notably, NPs and their analogs are responsible for over half of all approved drugs in current use. FDA data illustrated that NPs and their analogs represent more than one-third of all FDA-approved new lead molecules (Li and Lou, 2018). Many renowned scientists have contributed to this topic, which includes 13 papers, original articles along with review articles that give the readers of the Frontier in Pharmacology an updated and new appreciation of the tremendous role played by natural products in drug discovery. Hypericin is a penanthroperylenequinone which is a naturally occurring secondary metabolite produced by some Hypericum species. Hypericin was initially produced by H. perforatum (Brockmann et al., 1939), generally called St. John’s wort, which is one of the most important members of the Hypericum genus. Numerous cancers including myeloid leukemia, prostate cancer, glioblastoma, and breast cancer demonstrate powerful chemo resistance which is assisted by increased expression of numerous anti-apoptotic Bcl-2 proteins. Therefore one of the more important anti-cancer strategies would be to develop inhibitors of these Bcl-2 proteins, the BH3 mimetics. Stroffekova and coworkers (Doroshenko et al.) have demonstrated that hypericin can cause critical activity in the mitochondria function and cellular ultrastructure, and also cause distribution of Bcl2 proteins. The authors proposed that the possible mechanisms of cytotoxic effects OPEN ACCESS

Structures of low-energy conformers of caproleic acid (CA; 10:1 cis-9), oleic acid (OA; 18:1 cis-9),alinolenic acid (ALA; 18:3 cis-9,12,15 co-3), eicosapentaenoic acid (EPA; 20:5 cis-5,8,11,14,17 co-3), and docosahexaenoic acid (DHA; 22:6 cis-4,7,10,13,16,19 co-3) in the liquid state, based on detailed 1D NOE and density functional theory calculations of 1H NMR chemical shifts are presented. Transient 1D NOE experiments with variable mixing time showed significant through-space proximity of the CH2- COOH protons and the terminal CH3- groups. Variable temperature 1H NMR experiments revealed strong intermolecular centro-symmetric cyclic hydrogen bond interactions of the carboxylic groups of the monounsaturated oleic and caproleic acids (8(COOH) ti 12.0-12.4 ppm), ALA and EPA (8(COOH) ti 11.0 ppm). On the contrary, the carboxylic proton of DHA is strongly shielded with 8(COOH) ti 8.5 ppm. DFT calculations were interpreted in terms of aggregates of dimerized fatty acids with parallel and antiparallel interdigitated structures. The antiparallel arrangement was found to be in excellent agreement with experimental 1D NOE NMR data. For the dimeric DHA, a flip-flop process between a classical intermolecular centro-symmetric hydrogen bond through carboxylic groups and a novel intramolecular hydrogen bond between the carboxylic group and the terminal co-3 double bond is demonstrated. (c) 2023 Elsevier B.V. All rights reserved.

Medium- and long-chain saturated and unsaturated free fatty acids (FFAs) are known to bind to human serum albumin (HSA), the main plasma carrier protein. Atomic-level structural data regarding the binding mode in Sudlow’s sites I (FA7) and II (FA4, FA3) of the polyunsaturated ω-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), however, are largely unknown. Herein, we report the combined use of saturation transfer difference (STD) and Interligand NOEs for Pharmacophore Mapping (INPHARMA) NMR techniques and molecular docking calculations to investigate the binding mode of DHA and EPA in Sudlow’s sites Ι and ΙΙ of HSA. The docking calculations and the significant number of interligand NOEs between DHA and EPA and the drugs warfarin and ibuprofen, which are stereotypical ligands for Sudlow’s sites I and II, respectively, were interpreted in terms of competitive binding modes and the presence of two orientations of DHA and EPA at the binding sites FA7 and FA4. The exceptional flexibility of the long-chain DHA and EPA and the formation of strongly folded structural motives are the key properties of HSA–PUFA complexes.

Colocasia esculenta L. leaves are considered a by-product of taro cultivation and are discarded as environmental waste, despite their valuable phenolic composition. Their valorization to obtain value-added substances for medicinal, food, and cosmetic applications is the aim of the current work. An ultrasound-assisted extraction was developed for the environmentally friendly and sustainable isolation of taro leaf antioxidants using natural deep eutectic solvents (NaDESs). Among the utilized solvents, the NaDES based on betaine and ethylene glycol provided the best extraction efficiencies in terms of polyphenolic content and antioxidant activity. Multi-response optimization suggested a solvent-to-solid ratio of 10 mL g−1, a processing time of 60 min, an extraction temperature of 60 °C, and a water content of 33.8% (w/w) as optimal extraction parameters. Leaf extract obtained under these optimum operational parameters demonstrated a strong radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (65.80 ± 0.87%), a high ferric reducing antioxidant power (126.62 ± 1.92 μmol TE g−1 sample), and significant protection against oxidative stress-induced DNA damage. The chromatographic characterization of the optimum extract revealed its richness in flavonoids (flavones and flavonols). The outcomes of the present study suggest that the proposed method could serve as a highly efficient and green alternative for the recovery of polyphenols from agricultural wastes.

Saturation transfer difference (STD), inter-ligand NOEs (INPHARMA NMR), and docking calculations are reported for investigating specific binding sites of the high-affinity synthetic 7-nitrobenz-2-oxa-1,3-diazoyl-4-C12 fatty acid (NBD-C12 FA) with non-labeled human serum albumin (HSA) and in competition with the drugs warfarin and ibuprofen. A limited number of negative interligand NOEs between NBD-C12 FA and warfarin were interpreted in terms of a short-range allosteric competitive binding in the wide Sudlow’s binding site II (FA7) of NBD-C12 FA with Ser-202, Lys-199, and Trp-214 and warfarin with Arg-218 and Arg-222. In contrast, the significant number of interligand NOEs between NBD-C12 FA and ibuprofen were interpreted in terms of a competitive binding mode in Sudlow’s binding site I (FA3 and FA4) with Ser-342, Arg-348, Arg-485, Arg-410, and Tyr-411. NBD-C12 FA has the unique structural properties, compared to short-, medium-, and long-chain saturated and unsaturated natural free fatty acids, of interacting with well-defined structures with amino acids of both the internal and external polar anchor sites in Sudlow’s binding site I and with amino acids in both FA3 and FA4 in Sudlow’s binding site II. The NBD-C12 FA, therefore, interacts with novel structural characteristics in the drug binding sites I and II and can be regarded as a prototype molecule for drug development.

Molecular structures, in chloroform and DMSO solution, of the free fatty acids (FFAs) caproleic acid, oleic acid, α-linolenic acid, eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) are reported with the combined use of NMR and DFT calculations. Variable temperature and concentration chemical shifts of the COOH protons, transient 1D NOE experiments and DFT calculations demonstrate the major contribution of low molecular weight aggregates of dimerized fatty acids through intermolecular hydrogen bond interactions of the carboxylic groups, with parallel and antiparallel interdigitated structures even at the low concentration of 20 mM in CDCl3. For the dimeric DHA, a structural model of an intermolecular hydrogen bond through carboxylic groups and an intermolecular hydrogen bond between the carboxylic group of one molecule and the ω-3 double bond of a second molecule is shown to play a role. In DMSO-d6 solution, NMR and DFT studies show that the carboxylic groups form strong intermolecular hydrogen bond interactions with a single discrete solvation molecule of DMSO. These solvation species form parallel and antiparallel interdigitated structures of low molecular weight, as in chloroform solution. This structural motif, therefore, is an intrinsic property of the FFAs, which is not strongly affected by the length and degree of unsaturation of the chain and the hydrogen bond ability of the solvent.

Spectroscopic methods of molecular structure identification and analysis constitute part of inorganic, organic, analytical, and physical chemistry in both undergraduate and postgraduate chemistry curricula. Despite the importance and complexity of the relevant concepts, it is only recently that studies on spectroscopy have started to appear in the education literature. These studies have focused on student interpretation of spectra. The purpose of this study was to deal with further fundamental issues underlying spectroscopy. We first present students' perceptions of their knowledge about various aspects of spectroscopy such as the extent of their understanding of the basic concepts of UV, IR, NMR, and MS. In addition, we probed students' declarative knowledge about basic concepts and features of spectroscopy. The results showed that mass spectrometry was perceived to be the least understood method, while IR was perceived to be the best understood. Students considered their ability to identify the spectroscopic method used for obtaining a spectrum to be relatively satisfactory, as also was, but to a lesser extent, their ability to extract information from the spectrum. Students rated their understanding of the differences among the four spectroscopic methods as moderate. Concerning students' declarative knowledge about basic concepts and features of spectroscopy, such as the physical meaning of "wavenumber" in IR spectroscopy and of "part per million" in NMR spectroscopy, "performing integration", and the "resolving power" of a spectrometer, the results were mostly poor. Interestingly, a clear difference was observed between performance on questions at high versus basic levels of declarative knowledge.

Natural products bear a multivariate biochemical profile with antioxidant, anti-inflammatory, antibacterial, and antitumoral properties. Along with their natural sources, they have been widely used both as anti-aging and anti-melanogenic agents due to their effective contribution in the elimination of reactive oxygen species (ROS) caused by oxidative stress. Their anti-aging activity is mainly related to their capacity of inhibiting enzymes like Human Neutrophil Elastase (HNE), Hyaluronidase (Hyal) and Tyrosinase (Tyr). Herein, we accumulated literature information (covering the period 1965–2020) on the inhibitory activity of natural products and their natural sources towards these enzymes. To navigate this information, we developed a database and server termed ANTIAGE-DB that allows the prediction of the anti-aging potential of target compounds. The server operates in two axes. First a comparison of compounds by shape similarity can be performed against our curated database of natural products whose inhibitory potential has been established in the literature. In addition, inverse virtual screening can be performed for a chosen molecule against the three targeted enzymes. The server is open access, and a detailed report with the prediction results is emailed to the user. ANTIAGE-DB could enable researchers to explore the chemical space of natural based products, but is not limited to, as anti-aging compounds and can predict their anti-aging potential. ANTIAGE-DB is accessed online.

Ultrasonic synthesis of 26 amantadine derivatives, ( 3-28 ) including seven new compounds, are reported with significantly reduced synthesis time and increased percentage yield relative to literature data. Evaluation of the urease, and alpha-glucosidase enzyme inhibitory activities of all amantadine derivatives are being reported here for the first time. Three compounds were found to be potent urease inhibitors (IC50 = 9.32 +/- 1.01 mu M, to IC50 = 11.32 +/- 1.05 mu M) as compared to the standard drug acetohydroxamic acid (IC50 = 20.3 +/- 0.4 mu M). Five compounds were found to be potent inhibitors of alpha-glucosidase (IC50 = 40.63 +/- 1.70, to 50.07 +/- 1.73) as compared to standard drug acarbose (IC50 = 875.75 +/- 2.08 mu M). Kinetic studies were performed to investigate competitive and non-competitive inhibition of alpha- glucosidase enzymes and mixed type inhibition of urease enzyme. All compounds along with parent drug was checked for their cytotoxicity against human fibroblast (B.J.) cell line. Four compounds were found to be toxic, while the rest were nontoxic. Furthermore, in silico studies were performed to predict the binding interactions of the compounds at the active site of the enzymes. The two most active adamantane analogs against urease are those with m-and o-fluoro substitution due to specific interactions with CME592, HOH1918 and GLN635 (3.04, 2.74, and 3.21 A). Ortho analogs interact with GLN635 (3.04, 3.10 A). The two analogs having diflouro and tri flouro methyl group, showed a slight lower activity as compared to the first two compounds. This analysis clearly indicates the importance of position of fluoro group in urease inhibition activity. Similarly, in alpha- glucosidase inhibitors, three compounds with p-OCH3, ethyl groups, and di-fluoro were found to be the most active inhibitors in excellent agreement with experimental data. This study identifies new analogs with potent alpha-glucosidase and urease inhibitory activities. and, thus, may be of therapeutic importance.(c) 2022 Elsevier B.V. All rights reserved.