Ultrasound Assisted Green Synthesis of 2-Ethylhexyl Stearate: A Cosmetic Bio-lubricant.

The 2-ethylhexyl stearate is used as a bio-lubricant in various cosmetic products. The present study is focused on the biocatalyzed esterification of 2-ethylhexanol and stearic acid to form 2-ethylhexyl stearate catalyzed by Fermase CALB 10000 in the presence of ultrasound treatment. The maximum conversion (95.87%) was obtained at molar ratio of 2-ethylhexanol to stearic acid 2:1, enzyme amount of 2 % (w/w), power 80 W, duty cycle 50 % and temperature 50°C in comparatively short reaction time (3 h) in the presence of Fermase as a catalyst. At optimum conditions, it is observed that in the presence of ultrasound; the reaction time minimizes up to 4 h as compared to mechanical stirring method (7 h). The physiochemical properties for the 2-ethylhexyl palmitate were also evaluated.

Irreversible aggregation of alternating tetra-block-like amphiphile in water.

As a frontier topic of soft condensed matter physics, irreversible aggregation has drawn attention for a better understanding of the complex behavior of biomaterials. In this study, we have described the synthesis of an artificial amphiphilic molecule, an alternating tetra-block-like amphiphile, which was able to diversify its aggregate structure in water. The aggregated state of its aqueous dispersion was obtained by slow evaporation of the organic solvent at room temperature, and it collapsed irreversibly at ~ 50°C. By using a cryo-transmission electron microscope and a differential scanning calorimeter, it was revealed that two types of molecular nanostructures were formed and developed into submicro- and micrometer-sized fibrils in the aggregated material.

Preparation of Chiral Contiguous Epoxyaziridines and Their Regioselective Ring-Opening for Drug Syntheses.

Synthetically valuable chiral (aziridin-2-yl)oxirane-3-carbaldehydes bearing three consecutive functional groups including aziridine, epoxide, and aldehyde were prepared from the stereoselective epoxidation of (aziridin-2-yl)acrylaldehydes with H2 O2 using organocatalyst (2R)- or (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as organocatalyst. The regioselective ring opening of aziridines and epoxides enabled us to achieve the highly efficient asymmetric synthesis of the antibiotic edeine D fragment 3-hydroxy-4,5-diaminopenatanoic acid, an intermediate for the formal synthesis of non-proteinogenic amino acid (-)-galantinic acid, and for potent antifungal agent (+)-preussin, and the medicinally important framework 3-hydroxy-2-hydroxymethylpyrrolidine.

Synthesis and Application of a New Amphiphilic Antioxidant.

A new amphiphilic antioxidant (tannyl stearate) derived from reaction of tannic acid with stearic acid was synthesized in order to improve tannic acid solubility in lipid materials. This reaction gives many products having different degree of esterification (tannyl mono, di, tri, tetra, penta, hexa, hepta……stearate) which were separated using silica gel column chromatography and tentative identification was carried out using thin layer chromatography (TLC). The intrinsic viscosities (η) were used to differentiate between the different molecular weight of the produced esters1). Tannyl penta stearate is assumed to be the most suitable amphiphilic antioxidant derivative, where those derivatives with less degree of esterification would be less soluble in fat, and those of higher degree of esterification would exhaust more hydroxyl group that cause decreases of antioxidant activity. The structure of tannyl penta stearate was approved depending on its chemical analysis and spectral data (IR, H1 NMR,). The emulsification power of tannyl penta stearate was then determined according to method described by El-Sukkary et al.2), in order to prove its amphiphilic property. Then tannyl penta stearate was tested for its antioxidant and radical scavenging activities in three different manners, those are, lipid oxidation in sunflower oil using Rancimat, (DPPH) free radical scavenging and total antioxidant activity. {Pure tannic acid (T), butylhydroxyanisol (BHA) and butylhydroxytoluene (BHT) were used as reference antioxidant radical saving compounds}. Then tannyl penta stearate was added to sunflower oil, frying process was carried out and all physicochemical parameters of the oil were considered, and compared to other reference antioxidant in order to study the effect of this new antioxidant toward oil stability. Acute oral toxicity of the tannyl penta stearate was carried out using albino mice of 21-25 g body weight to determine its safety according to the method described by Goodman et al.3). Also liver and kidney functions of those mice were checked. Thus it could be concluded that the addition of tannyl penta stearate to frying oils offers a good protection against oxidation. The effectiveness of tannyl penta stearate as lipid antioxidant has been attributed mainly to its stability at high temperature. And according to acute lethal toxicity test tannyl penta stearate was found to be a safe compound that can be used as food additive.

Isotopologue profiling of triterpene formation under physiological conditions. Biosynthesis of lupeol-3-(3'-R-hydroxy)-stearate in Pentalinon andrieuxii.

The biosynthesis of lupeol-3-(3'R-hydroxy)-stearate (procrim b, 1) was investigated in the Mexican medicinal plant Pentalinon andrieuxii by (13)CO2 pulse-chase experiments. NMR analyses revealed positional enrichments of (13)C2-isotopologues in both the triterpenoid and the hydroxystearate moieties of 1. Five of the six isoprene units reflected a pattern with [1,2-(13)C2]- and [3,5-(13)C2]-isotopologues from the respective C5-precursors, IPP and DMAPP, whereas one isoprene unit in the ring E of 1 showed only the [3,5-(13)C2]-connectivity of the original C5-precursor, due to rearrangement of the dammarenyl cation intermediate during the cyclization process. The presence of (13)C2-isotopologues was indicative of [(13)C2]acetyl-CoA being the precursor units in the formation of the fatty acid moiety and of the triterpene via the mevalonate route. The observed labeling pattern was in agreement with a chair-chair-chair-boat conformation of the (S)-2,3-oxidosqualene precursor during the cyclization process, suggesting that the lupeol synthase from P. andrieuxii is of the same type as that from Olea europea and Taraxacum officinale, but different from that of Arabidopsis thaliana. The study shows that (13)CO2 pulse-chase experiments are powerful in elucidating, under in vivo conditions and in a single experiment, the biosynthesis of complex plant products including higher terpenes.

Design, synthesis and in vitro anticancer evaluation of a stearic acid-based ester conjugate.

AIM: Chemical synthesis and characterization of a lipophilic ester conjugate, propofol stearate and evaluation of its anticancer efficacy on human breast cancer cell lines MDA-MB-361, MCF-7 and MDA-MB-231. MATERIALS AND METHODS: The chemical structure of the synthesized conjugate was characterized by spectroscopic studies. Its anticancer potential was evaluated on the basis of growth inhibition, cancer cell adhesion and migration and apoptosis induction. RESULTS: Propofol stearate exhibited significant (p<0.05) growth inhibition of breast cancer cells in a concentration-dependent manner. MDA-MB-231 cells showed highest susceptibility towards the inhibitory effect of the conjugate. Moreover, treatment of MDA-MB-231 cancer cells with 25 µM propofol stearate potentially suppressed their adhesion (~34%) and migration (~41%), and induced apoptosis (~25%). CONCLUSION: Exogenously-applied stearic acid as an ester derivative, inhibits the growth of human breast cancer cells and shows a beneficial role in the treatment of breast cancer, in vitro.

Synthesis and spectral characterization of methyl 9(10)-dialkylphosphonostearates.

Dimethyl, diethyl, and di-n-butyl phosphites were reacted with methyl or ethyl oleates using thermally initiated radical reactions. Reactions were conducted with or without the presence of a dilauroyl peroxide initiator. The reactions gave mixture of isomers with the phosphorus attached at the 9 or 10 carbon of the stearates. High yields (94-97%) and high purity products (98-99% by GC) were obtained in the presence of the initiator, while without initiator, the reaction was very slow resulting in very low conversions (<50% after 6 days). The phosphonostearate products were positively identified and thoroughly characterized using GC with EI-MS, FTIR, and (1)H-, (13)C-, and (31)P NMR spectra. GC achieved only partial resolution of the positional isomers. Principal component analysis was applied to successfully separate the MS-EI spectra of fractions from the 9- and 10-isomers. A mechanism to explain the observed MS fragmentation pattern and the relative abundances is proposed. 2D-NMR data analysis was applied to assign values of (13)C- and (1)H NMR shifts as well as P-C and P-H splitting constants. The molecular volume and the refractive indices of the phosphonostearates were determined experimentally and were found to be in agreement with the computationally predicted values using the PM3 semi-empirical method and the group-contribution method of Bondi.

Optimization of lipase-catalyzed synthesis of fructose stearate using response surface methodology.

In this study, immobilized lipase-catalyzed esterification reaction between fructose and stearic acid was examined for the synthesis of a useful compound, fructose stearate, using response surface methodology. The increase of water content in the reaction medium was the negative effect while the increase in initial stearic acid/fructose molar ratio was the greatest positive effect on the yield. The highest fructose stearate yield was obtained as 65% in tert-butanol. The product yield was enhanced in 1-butyl-3-methylimidazolium trifluoromethanesulfonate obtained as 74% under the optimized conditions. The spectroscopic and elemental analysis methods showed that the esterification reaction is regioselective and the product is fructose monostearate.

Synthesis of a new amphiphilic glycodendrimer with antiviral functionality.

A new third generation amphiphilic glycodendrimer was synthesized from a stearylamide lysine dendrimer by condensation of the oligosaccharide moiety. By stepwise condensation and deprotection of di-boc lysine from a core of stearyl amide lysine, a third-generation stearylamide lysine dendrimer was constructed. Acetyl cellobiose and glucose units with the carboxylic acid at the end of alkyl chain attached to the reducing end of the sugar moiety was condensed with surface amino groups of the third generation lysine dendrimer, respectively, to give a new stearylamide acetylcellobiose and acetylglucose lysine dendrimers. The structural analysis was carried out using NMR, IR, and matrix-associated laser desorption/ionization time-of-flight (MALDI TOF) mass spectroscopies. After deacetylation to recover hydroxyl groups and subsequent sulfation, the third-generation sulfated cellobiose stearylamide lysine dendrimer was preliminarily found to have high anti-HIV activity at a 50% effective concentration (EC(50)) as low as 6.4 µg/ml and low cytotoxicity at a 50% cytotoxic concentration (CC(50)) as high as 1000 µg/ml, indicating that the dendrimer gave the enhancement of the functionality of oligosaccharides with low molecular weights. The glycodendrimer with a hydrophobic stearyl chain is immobilized on hydrophobic surfaces by hydrophobic interaction and is expected to provide a new biomedical material with the surface functionality of hydrophilic sulfated oligosaccharides.

Design and synthesis of fluorescence-labeled closo-dodecaborate lipid: its liposome formation and in vivo imaging targeting of tumors for boron neutron capture therapy.

The fluorescence-labeled closo-dodecaborane lipid (FL-SBL) was synthesized from (S)-(+)-1,2-isopropylideneglycerol as a chiral starting material. FL-SBL was readily accumulated into the PEGylated DSPC liposomes prepared from DSPC, CH, and DSPE-PEG-OMe by the post insertion protocol. The boron concentrations and the fluorescent intensities of the FL-SBL-labeled DSPC liposomes increased with the increase of the additive FL-SBL, and the maximum emission wavelength of the liposomes appeared at 531 nm. A preliminary in vivo imaging study of tumor-bearing mice revealed that the FL-SBL-labeled DSPC liposomes were delivered to the tumor tissue but not distributed to hypoxic regions.

Synthesis of fatty acid sterol esters using cholesterol esterase from Trichoderma sp. AS59.

We recently reported the characterization of novel cholesterol esterase (EC. 3.1.1.13) from Trichoderma sp. and preliminary work on sterol ester synthesis. In the present study, we further examined the enzyme ability to synthesize cholesterol esters from cholesterol and free fatty acids of various chain lengths, and compared the fatty acid specificity in synthesis with that in hydrolysis. The enzyme catalyzed the synthesis of medium- and long-chain fatty acid cholesterol esters, but failed to synthesize short-chain fatty acid esters. The fatty acid specificities in the synthesis and hydrolysis of cholesterol esters were entirely different from each other. Unlike other lipolytic enzymes, the enzyme was largely independent of water content in the synthesis of cholesterol oleate, and it achieved near-complete esterification in the presence of an equimolar excess of oleic acid. Of additional interest is the finding that the addition of n-hexane markedly enhanced the esterification activities on all the medium- and long-chain saturated fatty acids used. Based on these findings, we attempted to synthesize stigmasterol stearate as a food additive to lower cholesterol levels in blood plasma, and found that the enzyme catalyzed effective synthesis of the ester without the need of dehydration during the reaction, indicating the potential utility of the enzyme in the food industry.

Synthesis and application of 188Re-MN-16ET/Lipiodol in a hepatocellular carcinoma animal model.

INTRODUCTION: Hepatocellular carcinoma is the most common form of primary hepatic carcinoma. A new N(2)S(2) tetradentate ligand, N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl]octadecanoate (H(3)MN-16ET), was introduced and labeled with (188)Re to create (188)Re-MN-16ET in the Lipiodol phase. The potential of (188)Re-MN-16ET/Lipiodol for hepatoma therapy was evaluated in a hepatocellular carcinoma animal model of Sprague-Dawley rats implanted with the N1S1 cell line. METHODS: Synthesis of H(3)MN-16ET was described, and characterization was identified by infrared, nuclear magnetic resonance and mass spectra. We compared the effects of transchelating agents (glucoheptonate or tartaric acid) and a reducing agent (stannous chloride) on the complexing of (188)Re-perrhenate and H(3)MN-16ET. Twenty-four rats implanted with hepatoma were injected with 3.7 MBq/0.1 ml of (188)Re-MN-16ET/Lipiodol or (188)Re-MN-16ET via transcatheter arterial embolization. Biodistribution experiments and single-photon emission computed tomography imaging were performed to investigate tumor accumulation. RESULTS: H(3)MN-16ET was proved to easily conjugate with the Re isotope and showed good solubility in Lipiodol. The radiochemical purity of (188)Re-MN-16ET/Lipiodol with 10 mg tartaric acid and stannous chloride was shown to be more than 90%. The major distribution sites of (188)Re-MN-16ET in Sprague-Dawley rats were hepatoma and the liver. However, the radioactivity at the tumor site postadministered with (188)Re-MN-16ET was quickly decreased from 9.15±0.23 (at 1 h) to 2.71%±0.18% of injected dose/g (at 48 h). The biodistribution and micro-single-photon emission computed tomography/computed tomography image data showed that (188)Re-MN-16ET/Lipiodol was selectively retained at the tumor site, with 11.55±1.44, 13.16±1.46 and 10.67%±0.95% of injected dose/g at 1, 24 and 48 h postinjection, respectively. The radioactivity in normal liver tissue was high but significantly lower than that of the tumors. CONCLUSION: H(3)MN-16ET is a suitable tetradentate ligand for (188)Re labeling. From the animal data, we suggest that (188)Re-MN-16ET/Lipiodol has the potential to be a therapeutic radiopharmaceutical for hepatoma treatment.

Stearyl ferulate-based solid lipid nanoparticles for the encapsulation and stabilization of beta-carotene and alpha-tocopherol.

UVA exposure induces DNA damage that could result in skin carcinogenesis. Antioxidants are usually employed as protective agents to avoid this problem: in particular, both beta-carotene and alpha-tocopherol can protect the skin against UVA-induced damage. It is well known that the photochemical instability of these compounds has been a limiting factor for their applications to protect skin. In this study, stearyl ferulate-based solid lipid nanoparticles (SF-SLNs), as vehicles for beta-carotene and alpha-tocopherol, were formulated to improve the stability of these compounds. The SF-SLNs were characterized for entrapment efficiency, size and shape together with their cytotoxicity and capability to inhibit lipid peroxidation. After treatment with a pro-oxidant and/or exposition to sunlight the antioxidants entrapped in SF-SLNs were extremely stable. The results highlighted how SF-SLNs represent a suitable vehicle for beta-carotene and alpha-tocopherol stabilizing and protecting them from degradation. A dermatological formulation in order to prevent skin damages is, therefore, suggested.

Synthesis of isoamyl laurate and isoamyl stearate in supercritical carbon dioxide.

The synthesis of isoamyl laurate and isoamyl stearate was studied in supercritical carbon dioxide with three lipases, Novozym 435, Lipolase 100T, and Candida rugosa. The maximum conversion of 37% and 53%, respectively for isoamyl laurate and isoamyl stearate was obtained when Novozym 435 was used. The effect of various parameters such as molar ratio of alcohol to acid, presence of water, time and temperature was investigated. An optimum temperature of 40-45 degrees C was observed for all reactions. The kinetics of reactions was fast and equilibrium was achieved in 2-3 h. Although the presence of excess alcohol did not reduce conversion, excess water reduced conversion significantly.

Synthesis of sn-1 functionalized phospholipids as substrates for secretory phospholipase A2.

Secretory phospholipase A2 (sPLA2) represents a family of small water-soluble enzymes that catalyze the hydrolysis of phospholipids in the sn-2 position liberating free fatty acids and lysophospholipids. Herein we report the synthesis of two new phospholipids (1 and 2) with bulky allyl-substituents attached to the sn-1 position of the glycerol backbone. The synthesis of phospholipids 1 and 2 is based upon the construction of a key aldehyde intermediate 3 which locks the stereochemistry in the sn-2 position of the final phospholipids. The aldehyde functionality serves as the site for insertion of the allyl-substituents by a zinc mediated allylation. Small unilamellar liposomes composed of phospholipids 1 and 2 were subjected to sPLA2 activity measurements. Our results show that only phospholipid 1 is hydrolyzed by the enzyme. Molecular dynamics simulations revealed that the lack of hydrolysis of phospholipid 2 is due to steric hindrance caused by the bulky side chain of the substrate allowing only limited access of water molecules to the active site.

Catechin conjugated with fatty acid inhibits DNA polymerase and angiogenesis.

Catechins in green tea have anticancer and antiangiogenesis activities, with epigallocatechin-3-gallate (EGCG) being the most potent antiangiogenic tea catechin. This study examined whether chemical modification of catechin enhanced anticancer and antiangiogenic effects. Catechin, conjugated with fatty acid (acyl-catechin), strongly inhibited DNA polymerase, HL-60 cancer cell growth, and angiogenesis. Catechin conjugated with stearic acid [(2R,3S)-3',4',5,7-tetrahydroxyflavan-3-yl octadecanoate; catechin-C18] was the strongest inhibitor in DNA polymerase alpha and beta and angiogenesis assays. Catechin-C18 also suppressed human endothelial cell (HUVEC) tube formation on the reconstituted basement membrane, suggesting that it affected not only DNA polymerases but also signal transduction pathways in HUVECs. These data indicate that acyl-catechins target both DNA polymerases and angiogenesis as anticancer agents. These results suggest that acylation of catechin is an effective chemical modification to improve the anticancer activity of catechin.

Non-adhesive cyanoacrylate as an embolic material for endovascular neurosurgery.

Endovascular neurosurgery is now becoming available as one of strategies for the treatment of cerebro-spinal arterio-venous malformations and aneurysms. For this treatment, a microcatheter is advanced into or close to a lesion and then an embolic material is administered through it to obliterate the lesion. N-butyl-2-cyanoacrylate (NBCA) has preferentially been used as an embolic material in Europe and America. However, its exceptionally strong adhesive force sometimes causes adhesion between the tip of the microcatheter and the artery. In this study, a new non-adhesive cyanoacrylate, isostearyl-2-cyanoacrylate (ISCA), was developed. It carries a long hydrophobic side isostearyl group with lower reactivity and adhesion than other cyanoacrylates. Its polymerization rate is, however, too low to obliterate a vascular lesion with a rapid blood flow. To increase the polymerization rate. ISCA was mixed with NBCA. As a result, the adhesive force of the mixture became extremely low, compared with that of NBCA. The viscosity of the mixture was low enough to allow its' use as an embolic material. Tissue reactions against the mixture was milder than those against NBCA. Radio-angiography became possible by mixing further with Lipiodol. The evaluation of this new embolic material with a rabbit renal artery showed that the obliteration effect of the mixture of ISCA and NBCA was excellent to use as an embolic material for clinical applications.

Synthetic dipeptide, N-stearoyl-D-Ser-L-Pro-OEt, induces release of tissue-type plasminogen activator in cultured cells and in experimental animals.

The tissue-type plasminogen activator (t-PA)-releasing action of synthetic dipeptides containing Gly, Ser or Pro was investigated. Among 10 dipeptides, Boc-L-Ser-L-Pro-OH and H-L-Ser-L-Pro-OH induced t-PA release in vitro, but the others were inactive. Since Boc-L-Ser-L-Pro-OH was more effective than H-L-Ser-L-Pro-OH, 7 related dipeptides with N-acylation were synthesized. Five of them enhanced the release of t-PA; N-stearoyl-L-Ser-L-Pro-OH (FK-5) had the greatest effect. Four compounds were further examined for activity to enhance the release of t-PA in rats. FK-5 produced a two-fold increase in fibrinolytic activity, and N-palmitoyl-L-Ser-L-Pro-OH (FK-4) also markedly enhanced the release of t-PA. Since FK-5 caused severe hemolysis, 7 analogues of FK-5 were synthesized. All of them enhanced the release of t-PA from melanoma (Bowes) cells. In rats, FK-5, N-stearoyl-D-Ser-L-Pro-OH (FK-8) and N-stearoyl-D-Ser-L-Pro-OEt (FK-10) enhanced the fibrinolytic activity two-fold. FK-5 and FK-8 also exhibited strong hemolytic activity, but FK-10 did not induce hemolysis. Therefore, FK-10 was examined in rabbits. After the injection of this compound, the fibrinolytic activity in the euglobulin fraction was markedly enhanced without accompanying hemolysis. Thus, FK-10 potently enhances fibrinolytic activity both in vitro and in vivo.

Preparation, characterization, and dissolution kinetics of two novel albuterol salts.

The possibility of producing slowly dissolving albuterol salts was investigated as a potential means of extending the duration of action of the drug following aerosol delivery to the lung. Albuterol adipate and stearate were precipitated from alcoholic solutions of albuterol and adipic or stearic acids, respectively. Differential scanning calorimetry and hot stage microscopy showed that albuterol adipate and stearate produced single melting endotherms at 182 and 116 degrees C, respectively, which were distinct from those of albuterol (158 degrees C), adipic acid (152 degrees C), and stearic acid (70 degrees C). The aqueous solubilities of albuterol free base, sulfate, adipate, and stearate were 15.7, 250, 353, and 0.6 mg . mL-1, respectively, at room temperature. Only the solubilities of the adipate and the stearate increased significantly when the temperature was elevated to 37 degrees C (452.5 and 1.4 mg . mL-1, respectively). With a rotating disk dissolution method, albuterol free base, sulfate, and adipate were found to have intrinsic dissolution rates of 1.1, 20.4, and 24.0 mg . min-1 . cm-2, respectively, in pH 7.4 phosphate buffer at 37 degrees C. Albuterol stearate dissolved much more slowly and in a nonlinear fashion; this was explained by the deposition of a stearate-rich layer on the dissolving surface of the compacted salt.

The preparation and some physical properties of ten methyl dithiastearate isomers.

Ten methyl dithiastearate isomers, containing 0-4 methylene groups between the two sulfur atoms in each of the molecules, were synthesized using a one-pot synthesis approach. The preparation of the tetra-methylene (3,4), tri-methylene (5,6) and di-methylene (7,8) interrupted methyl dithiastearate isomers involved the asymmetric coupling of n-bromoalkanes, alkanedithiols and omega-bromoalkanoic acids. The mono-methylene interrupted isomers (9,10) were prepared from dibromethane, which was allowed to couple with n-alkanethiols and omega-mercaptoalkanoic acids. For the non-methylene interrupted isomers (11,12), n-alkanethiols were initially converted to the sulfenyl bromide and reacted with omega-mercaptoalkanoic acids. These sulfur-containing fatty ester analogues were found to be more polar and with longer retention times than methyl stearate when analyzed by TLC (silica) and GC (SE-30) respectively. In the 1H-NMR analysis the shifts of the protons of CH2 groups adjacent to the sulfur atoms in 3-6 appeared at 2.50-2.60 (t) delta, while the tri-methylene interrupted isomers (5,6) furnished an additional characteristic signal at 1.84 (quintet) delta arising from the protons of the beta-positioned CH2 between the sulfur atoms. Compounds 7-8 gave a singlet at 2.70 delta, while 9,10 also gave a singlet at 3.64-3.65 delta for the protons of the CH2 group situated between the sulfur atoms. In compounds 11,12 the shift of the protons of the CH2 adjacent to the sulfur atom appeared at 2.68 (t) delta.(ABSTRACT TRUNCATED AT 250 WORDS)