We report the synthesis of a structurally diverse library of chiral Nβ-substituted 1,2-diazetidin-3-ones by a 4-center 3-component Ugi reaction comprising unprotected α-hydrazino acids. Various ...isocyanides and carbonyl compounds and both aldehydes and ketones were utilized. In addition, postcondensation modifications at three different sites have been demonstrated.
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We describe the utilization of bis-isopropylidene-protected d-fructose-derived aldehyde in the Passerini reaction with various acids and isocyanides. A library of densely functionalized glycomimetics ...bearing up to 3 carbohydrate units was obtained in high yields and diastereoselectivities. The configuration of the newly formed stereocenter was determined and the diastereoselectivity was rationalized by DFT calculations.
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Because of its quantitative character and capability for high-throughput screening, 1H nuclear magnetic resonance (NMR) spectroscopy is used extensively in the profiling of biofluids such as urine ...and blood plasma. However, the narrow frequency bandwidth of 1H NMR spectroscopy leads to a severe overlap of the spectra of components present in the complex mixtures such as biofluids. Therefore, 1H NMR-based metabolomics analysis is focused on targeted studies related to concentrations of the small number of metabolites. Here, we propose a library-based approach to quantify proportions of overlapping metabolites from 1H NMR mixture spectra. The method boils down to the linear non-negative least squares (NNLS) problem, whereas proportions of the pure components contained in the library stand for the unknowns. The method is validated on an estimation of the proportions of (i) the 78 pure spectra, presumably related to type 2 diabetes mellitus (T2DM), from their synthetic linear mixture; (ii) metabolites present in 62 1H NMR spectra of urine of subjects with T2DM and 62 1H NMR spectra of urine of control subjects. In both cases, the in-house library of 210 pure component 1H NMR spectra represented the design matrix in the related NNLS problem. The proposed method pinpoints 63 metabolites that in a statistically significant way discriminate the T2DM group from the control group and 46 metabolites discriminating control from the T2DM group. For several T2DM-discriminative metabolites, we prove their presence by independent analytical determination or by pointing out the corresponding findings in the published literature.
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The aim of this study was to assess the gelling potential of chiral oxalamide derivatives in vegetable oils. Special emphasis was given to the potential applications of the examined oil gels as ...sustained delivery systems and as fat substitutes in food products. The applicability of oil gelators is envisaged in food, cosmetics, and the pharmaceutical industry. The regulations requiring the elimination of saturated fats and rising concerns among consumers health motivated us to investigate small organic molecules capable of efficiently transforming from liquid oil to a gel state. The oxalamide organogelators showed remarkable gelation efficiency in vegetable oils, thermal and mechanical stability, self-healing properties, and a long period of stability. The physical properties of the gels were analysed by TEM microscopy, DSC calorimetry, and oscillatory rheology. The controlled release properties of acetylsalicylic acid, ibuprofen, and hydrocortisone were analysed by the LC–MS method. The influence of the oil type (sunflower, soybean, and olive oil) on gelation efficiency of diverse oxalamide derivatives was examined by oscillatory rheology. The oxalamide gelators showed thermoreversible and thixotropic properties in vegetable oils with a minimum gelation concentration of just 0.025 wt%. The substitution of palm fats with gelled sunflower oil applied in cocoa and milk spreads at gelator concentrations lower than 0.2 wt% have shown promising viscoelastic properties compared to that of the original food products.
We applied a multicomponent approach to access a library of densely functionalized homo- and hetero-multivalent glycomimetics comprising aldehyde, amine, and isocyanide components related to ...isopropylidene-protected d-fructose, l-sorbose, d-galactose, and d-allose. Passerini products were obtained in very good yields (up to 78%) and high diastereoselectivities (up to 98:2). Three types of products were obtained by the Ugi reaction; along with the “classical” four-component product, α-acylaminoamides, a three-component α-aminoamides, and a four- component α-aminoacylamides were isolated. The presence of multiple pathways is rationalized by the structure of the imidate intermediate, mainly influenced by the amine component.
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A synthetic strategy for the Ugi reaction on amino-β-lactam synthon 1 was developed. The Ugi reaction products 5 were obtained in satisfactory yields (47–78%) and generally, low diastereoselectivity ...(up to 72:28 dr). In case of Ugi products 5 derived from cyclohexylcarbaldehyde and amino-β-lactam 1, the reaction yields were lower (38–61%) but the products were obtained in high diastereoselectivity (>95:5).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Lectins, carbohydrate-binding proteins, play important functions in all forms of life from bacteria and viruses to plants, animals, and humans, participating in cell–cell communication and pathogen ...binding. In an attempt to modify lectin functions, artificial lectin ligands were made usually as big dendrimeric or cluster multivalent glycomimetic structures. Here we synthesized a novel set of glycomimetic ligands through protection/deprotection multicomponent reactions (MCR) approach. Multivalent di-and tri-carbohydrate glycomimetics containing
d
-fructose,
d
-galactose, and
d
-allose moieties were prepared in 63–96% yield. MCR glycomimetics demonstrated different binding abilities for plant lectins Con A and UEA I, and human galectin-3. Information gained about the influence of molecule structure, multivalency and optical purity on the lectin binding ability can be used in lectin detection and sensitivity measurements to further facilitate understanding of carbohydrate recognition process.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Predicting antitumor activity of compounds using regression models trained on a small number of compounds with measured biological activity is an ill-posed inverse problem. Yet, it occurs very often ...within the academic community. To counteract, up to some extent, overfitting problems caused by a small training data, we propose to use consensus of six regression models for prediction of biological activity of virtual library of compounds. The QSAR descriptors of 22 compounds related to the opioid growth factor (OGF, Tyr-Gly-Gly-Phe-Met) with known antitumor activity were used to train regression models: the feed-forward artificial neural network, the k-nearest neighbor, sparseness constrained linear regression, the linear and nonlinear (with polynomial and Gaussian kernel) support vector machine. Regression models were applied on a virtual library of 429 compounds that resulted in six lists with candidate compounds ranked by predicted antitumor activity. The highly ranked candidate compounds were synthesized, characterized and tested for an antiproliferative activity. Some of prepared peptides showed more pronounced activity compared with the native OGF; however, they were less active than highly ranked compounds selected previously by the radial basis function support vector machine (RBF SVM) regression model. The ill-posedness of the related inverse problem causes unstable behavior of trained regression models on test data. These results point to high complexity of prediction based on the regression models trained on a small data sample.
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C -Glycosyl amino acids are a group of C -glycosides in which a carbohydrate molecule is attached to the side chain or backbone of the amino acid via a C–C bond. Despite the numerous methods that ...have been developed for their synthesis, the C -glycosyl α-amino acids and their oligomers are relatively unexplored. In this work, we presented a protocol for the synthesis of oligomers containing alternating C -glycosyl α-amino acids and proteinogenic α-amino acids. The methodology is based on the modification of α-acyloxyamides obtained from the Passerini reaction using α- d -galactopyranose- and α- l -sorbofuranose-derived aldehydes as C -glycosyl donors. The protocol enabled the synthesis of homo- and heterochiral tetramers, and homo- and heterovalent tetramers in very good yields.
Scientists of all kinds have long been intrigued by the nature, action and potential of natural toxins that possess exceptional antibacterial and anticancer activities. These compounds, named ...enediynes, are among the most effective chemotherapeutic agents known. Often compared with intelligent weapons, due to the unique structure and sophisticated mechanism by which they destroy double-helical DNA, enediyne antibiotics are nowadays the most promising leaders in the anticancer therapy. Apart from their diversity, enediyne compounds share some structural and functional similarities. One fragment of a structure is responsible for the recognition and transport, another part acts as molecular trigger while the third, reactive enediyne unit, undergoes Bergman cycloaromatization and causes DNA breakage. Members of the enediyne family are already in clinical use to treat various cancers, but more general use is limited by their complex structure, which makes them formidable targets for synthetic chemists. There are three main approaches in the design of new enediyne-related compounds: improvement of enediyne "warheads", increasing the selectivity and control of chemical or photo-induced activation. This paper gives an overview of naturally occurring enediynes, their mode of action and efforts undertaken to design artificial enediyne-related DNA cleaving agents.
Znanstvenici raznih profila dugo su bili intrigirani prirodom, mehanizmom djelovanja i potencijalom prirodnih toksina s izuzetnom antibakterijskom i antitumorskom aktivnošću. Ti spojevi, nazvani endiini, danas su među najaktivnijim kemoterapeutskim agensima. Često uspoređivani s inteligentnim oružjem, zbog jedinstvene strukture i sofisticiranog mehanizma kojim uništavaju molekulu DNA, endiinski antibiotici danas predstavljaju vodeće spojeve u antitumorskoj terapiji. Predstavnici endiinske skupine spojeva su u kliničkoj primjeni, premda je njihova primjena ograničena složenom strukturom, što ih čini zahtjevnim ciljem za sintetske kemičare. Ovaj rad daje pregled prirodnih endiina, mehanizma njihova djelovanja i sintetskih analoga sa sposobnošću cijepanja molekule DNA.
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