Search Results (13)

In the field of medicinal chemistry, the introduction of silylated groups is an important strategy to alter the activity, selectivity, and pharmacokinetics of compounds based on the diverse traits of silicon, including atomic size, electronegativity, and hydrophobicity. The hydroxy group on C-9 or C-9 and C-10 of hydroxystearic acids have been functionalized as t-butyl dimethyl silyl ether. The target compounds have been fully characterized and tested for in vitro cytotoxicity in tumor cells HT29, HCT116, CaCo2, HeLa, MCF7, U2OS, and Jurkat J6 and normal I407 cells. In particular, the silyl derivative of (R)-9-hydroxystearic acid was more active in colon cancer cells. Analyses of cell proliferation, oxidative cell status, histones post-translational modifications, protein phosphorylation, gene expression, and DNA damage were performed to obtain information on the antitumor properties of the new molecules in comparison with the unmodified (R)-9-hydroxystearic acid’s previously studied effects. Our results suggest that the incorporation of a silyl functionality may be a useful tool for the structural development of new pharmaceutically active compounds against colon cancer. Full article

Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression. Full article

This study examines the structures of soft surfactant-based biomaterials which can be tuned by temperature. More precisely, investigated here is the behavior of stearic acid (SA) and 12-hydroxystearic acid (12-HSA) aqueous mixtures as a function of temperature and the 12-HSA/SA molar ratio (R). Whatever R is, the system exhibits a morphological transition at a given threshold temperature, from multilamellar self-assemblies at low temperature to small micelles at high temperature, as shown by a combination of transmittance measurements, Wide Angle X-ray diffraction (WAXS), small angle neutron scattering (SANS), and differential scanning calorimetry (DSC) experiments. The precise determination of the threshold temperature, which ranges between 20 °C and 50 °C depending on R, allows for the construction of the whole phase diagram of the system as a function of R. At high temperature, the micelles that are formed are oblate for pure SA solutions (R = 0) and prolate for pure 12-HSA solutions (R = 1). In the case of mixtures, there is a progressive continuous transition from oblate to prolate shapes when increasing R, with micelles that are almost purely spherical for R = 0.33. Full article

Here, we describe the behavior of mixtures of stearic acid (SA) and its hydroxylated counterpart 12-hydroxystearic acid (12-HSA) in aqueous mixtures at room temperature as a function of the 12-HSA/SA mole ratio R. The morphologies of the self-assembled aggregates are obtained through a multi-structural approach that combines confocal and cryo-TEM microscopies with small-angle neutron scattering (SANS) and wide-angle X-ray scattering (WAXS) measurements, coupled with rheology measurements. Fatty acids are solubilized by an excess of ethanolamine counterions, so that their heads are negatively charged. A clear trend towards partitioning between the two types of fatty acids is observed, presumably driven by the favorable formation of a H-bond network between hydroxyl OH function on the 12th carbon. For all R, the self-assembled structures are locally lamellar, with bilayers composed of crystallized and strongly interdigitated fatty acids. At high R, multilamellar tubes are formed. The doping via a low amount of SA molecules slightly modifies the dimensions of the tubes and decreases the bilayer rigidity. The solutions have a gel-like behavior. At intermediate R, tubes coexist in solution with helical ribbons. At low R, local partitioning also occurs, and the architecture of the self-assemblies associates the two morphologies of the pure fatty acids systems: they are faceted objects with planar domains enriched in SA molecules, capped with curved domains enriched in 12-HSA molecules. The rigidity of the bilayers is strongly increased, as well their storage modulus. The solutions remain, however, viscous fluids in this regime. Full article

Currently, there is renewed interest in using fatty acid soaps as surfactants. Hydroxylated fatty acids are specific fatty acids with a hydroxyl group in the alkyl chain, giving rise to chirality and specific surfactant properties. The most famous hydroxylated fatty acid is 12-hydroxystearic acid (12-HSA), which is widely used in industry and comes from castor oil. A very similar and new hydroxylated fatty acid, 10-hydroxystearic acid (10-HSA), can be easily obtained from oleic acid by using microorganisms. Here, we studied for the first time the self-assembly and foaming properties of R-10-HSA soap in an aqueous solution. A multiscale approach was used by combining microscopy techniques, small-angle neutron scattering, wide-angle X-ray scattering, rheology experiments, and surface tension measurements as a function of temperature. The behavior of R-10-HSA was systematically compared with that of 12-HSA soap. Although multilamellar micron-sized tubes were observed for both R-10-HSA and 12-HSA, the structure of the self-assemblies at the nanoscale was different, which is probably due to the fact that the 12-HSA solutions were racemic mixtures, while the 10-HSA solutions were obtained from a pure R enantiomer. We also demonstrated that stable foams based on R-10-HSA soap can be used for cleaning applications, by studying spore removal on model surfaces in static conditions via foam imbibition. Full article

Recently, we described the preparation of the recombinant oleate hydratase from Lactobacillus rhamnosus ATCC 53103. We observed that the purified C-terminal His-tagged enzyme was completely inactive and the catalytic activity was partially restored only in presence of a large amount of flavin adenine dinucleotide (FAD). In the present work, we assess that this hydratase in the presence of the reduced form of flavin adenine dinucleotide (FADH₂) is at least one hundred times as active as in the presence of the same concentration of FAD. By means of two different biochemical processes, we demonstrated unambiguously that oleate hydratase from Lactobacillus rhamnosus ATCC 53103 is a FADH₂-dependent enzyme. As a first relevant application of this discovery, we devised a preparative procedure for the stereoselective synthesis of (R)-10-hydroxystearic acid. Accordingly, the hydration of oleic acid (up to 50 g/L) is performed on a multigram scale using the recombinant hydratase and FADH₂ generated in situ as cofactor. The produced (R)-10-hydroxystearic acid (ee > 97%) precipitates from the reaction solvent (water/glycerol/ethanol) and is conveniently recovered by simple filtration (>90% yield). Full article

In this work, the transesterification of methyl estolides (ME) extracted from the lipid component present in the sewage scum was investigated. Methyl 10-(R)-hydroxystearate (Me-10-HSA) and Fatty Acid Methyl Esters (FAMEs) were obtained in a single step. A three-level and four factorial Box–Behnken experimental design were used to study the effects of methanol amounts, catalyst, temperature, and reaction time on the transesterification reaction using aluminum chloride hexahydrate (AlCl₃·6H₂O) or hydrochloric acid (HCl) as catalysts. AlCl₃·6H₂O was found quite active as well as conventional homogeneous acid catalysts as HCl. In both cases, a complete conversion of ME into Me-10-HSA and FAMEs was observed. The products were isolated, quantified, and fully characterized. At the end of the process, Me-10-HSA (32.3%wt) was purified through a chromatographic separation and analyzed by NMR. The high enantiomeric excess (ee > 92%) of the R-enantiomer isomer opens a new scenario for the valorization of sewage scum. Full article

The chiral (R)-10-hydroxystearic acid ((R)-10-HSA) is a positional homologue of both (R)-12-HSA and (R)-9-HSA with the OH group in an intermediate position. While (R)-12-HSA is one of the best-known low-molecular-weight organogelators, (R)-9-HSA is not, but it forms crystals in several solvents. With the aim to gain information on the structural role of hydrogen-bonding interactions of the carbinol OH groups, we investigated the behavior of (R)-10-HSA in various solvents. This isomer displays an intermediate behavior between (R)-9 and (R)-12-HSA, producing a stable gel exclusively in paraffin oil, while it crystallizes in other organic solvents. Here, we report the X-ray structure of a single crystal of (R)-10-HSA as well as some structural information on its polymorphism, obtained through X-ray Powder Diffraction (XRPD) and Infrared Spectroscopy (IR). This case study provides new elements to elucidate the structural determinants of the microscopic architectures that lead to the formation of organogels of stearic acid derivatives. Full article

Different microbial strains are able to transform oleic acid (OA) into 10-hydroxystearic acid (10-HSA) by means of the catalytic activity of the enzymes oleate hydratase (EC 4.2.1.53). Lactobacillus rhamnosus ATCC 53103 performs this biotransformation with very high stereoselectivity, affording enantiopure (R)-10-HSA. In this work, we cloned, in Escherichia coli, the oleate hydratase present in the above-mentioned probiotic strain. Our study demonstrated that the obtained recombinant hydratase retains the catalytic properties of the Lactobacillus strain but that its activity was greatly affected by the expression procedure. According to our findings, we devised a reliable procedure for the hydration of oleic acid using a recombinant E. coli whole-cell catalyst. We established that the optimal reaction conditions were pH 6.6 at 28 °C in phosphate buffer, using glycerol and ethanol as co-solvents. According to our experimental protocol, the biocatalyst does not show significant substrate inhibition as the hydration reaction can be performed at high oleic acid concentration (up to 50 g/L). Full article

In this work, we studied the biotechnological potential of thirteen probiotic microorganisms currently used to improve human health. We discovered that the majority of the investigated bacteria are able to catalyze the hydration reaction of the unsaturated fatty acids (UFAs). We evaluated their biocatalytic activity toward the three most common vegetable UFAs, namely oleic, linoleic, and linolenic acids. The whole-cell biotransformation experiments were performed using a fatty acid concentration of 3 g/L in anaerobic conditions. Through these means, we assessed that the main part of the investigated strains catalyzed the hydration reaction of UFAs with very high regio- and stereoselectivity. Our biotransformation reactions afforded almost exclusively 10-hydroxy fatty acid derivatives with the single exception of Lactobacillus acidophilus ATCC SD5212, which converted linoleic acid in a mixture of 13-hydroxy and 10-hydroxy derivatives. Oleic, linoleic, and linolenic acids were transformed into (R)-10-hydroxystearic acid, (S)-(12Z)-10-hydroxy-octadecenoic, and (S)-(12Z,15Z)-10-hydroxy-octadecadienoic acids, respectively, usually with very high enantiomeric purity (ee > 95%). It is worth noting that the biocatalytic capabilities of the thirteen investigated strains may change considerably from each other, both in terms of activity, stereoselectivity, and transformation yields. Lactobacillus rhamnosus ATCC 53103 and Lactobacillus plantarum 299 V proved to be the most versatile, being able to efficiently and selectively hydrate all three investigated fatty acids. Full article

9-Hydroxystearic acid (9-HSA) is an endogenous cellular lipid that possesses antiproliferative and selective effects against cancer cells. A series of derivatives were synthesized in order to investigate the effect of the substituent in position 9 and on the methyl ester functionality on the biological activity. The two separate enantiomers of methyl 9-hydroxystearate and of methyl 9-aminostearate showed antiproliferative activity against the HT29 cell line. This indicates the importance of position 9 groups being able to make hydrogen bonding with the molecular target. Further, this effect must be preserved when the carboxy group of 9-HSA is esterified. The biological tests showed that the amines, contrarily to methyl esters, resulted in cytotoxicity. A deep investigation on the effect of methyl (R)-9-hydroxystearate on HT29 cells showed an antiproliferative effect acting through the CDKN1A and MYCBP gene expression. Full article

(R)-9-hydroxystearic acid, (R)-9-HSA, is a chiral nonracemic hydroxyacid of natural origin possessing interesting properties as an antiproliferative agent against different cancer types. Considering its potential application for medical and pharmaceutical purposes, the structures and rheological properties of (R)-9-HSA were investigated. Oscillatory rheology measurements reveal that (R)-9-HSA gels only paraffin oil, with less efficiency and thermal stability than its positional isomer (R)-12-HSA. Conversely, (R)-9-HSA affords crystals from methanol, acetonitrile, and carbon tetrachloride. The single crystal structures obtained both at 293 K and 100 K show non-centrosymmetric twisted carboxylic acid dimers linked at the midchain OHs into long, unidirectional chains of hydrogen bonds, owing to head-tail ordering of the molecules. Synchrotron X-ray powder diffraction experiments, performed on the solids obtained from different solvents, show the occurrence of polymorphism in paraffin oil and through thermal treatment of the solid from methanol. Full article

Natural hydroxy fatty acids are relevant starting materials for the production of a number of industrial fine chemicals, such as different high-value flavour ingredients. Only a few of the latter hydroxy acid derivatives are available on a large scale. Therefore, their preparation by microbial hydration of unsaturated fatty acids, affordable from vegetable oils, is a new biotechnological challenge. In this study, we describe the use of the probiotic bacterium Lactobacillus rhamnosus (ATCC 53103) as whole-cell biocatalyst for the hydration of the most common unsaturated octadecanoic acids, namely oleic acid, linoleic acid, and linolenic acid. We discovered that the addition of the latter fatty acids to an anaerobic colture of the latter strain, during the early stage of its exponential growth, allows the production of the corresponding mono-hydroxy derivatives. In these experimental conditions, the hydration reaction proceeds with high regio- and stereoselectivity. Only 10-hydroxy derivatives were formed and the resulting (R)-10-hydroxystearic acid, (S)-(12Z)-10-hydroxy-octadecenoic acid, and (S)-(12Z,15Z)-10-hydroxy-octadecadienoic acid were obtained in very high enantiomeric purity (ee > 95%). Although overall conversions usually do not exceed 50% yield, our biotransformation protocol is stereoselective, scalable, and holds preparative significance. Full article