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Glycolipid surfactants are biocompatible and biodegradable compounds characterized by potential applications in various sectors including pharmaceuticals, cosmetics, agriculture, and food production. A specific overview regarding synthetic methodologies and properties of 6′-lactose-based surfactants is presented herein, particularly all the synthet...
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The delivery of therapeutics across biological membranes (e.g., mucosal barriers) by avoiding invasive routes (e.g., injection) remains a challenge in the pharmaceutical field. As such, there is the need to discover new compounds that act as drug permeability enhancers with a favorable toxicological profile. A valid alternative is represented by th...
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... In the food industry, surfactants can be used as bio-emulsifiers and preservatives [12]. At the agricultural level, surfactants are described as acting against phytopathogenic fungi or as seed fertility enhancers, or as antimicrobial agents, like 6 ′ -O-lactose esters [13][14][15]. In the literature, in biosurfactants based on carbohydrate platforms, either mono-or oligosaccharides are found, and lipids are major constituents. ...
Carbohydrate-based surfactants are amphiphilic compounds containing hydrophilic moieties linked to hydrophobic aglycones. More specifically, carbohydrate esters are biosourced and biocompatible surfactants derived from inexpensive renewable raw materials (sugars and fatty acids). Their unique properties allow them to be used in various areas, such as the cosmetic, food, and medicine industries. These multi-applications have created a worldwide market for biobased surfactants and consequently expectations for their production. Biobased surfactants can be obtained from various processes, such as chemical synthesis or microorganism culture and surfactant purification. In accordance with the need for more sustainable and greener processes, the synthesis of these molecules by enzymatic pathways is an opportunity. This work presents a state-of-the-art lipase action mode, with a focus on the active sites of these proteins, and then on four essential parameters for optimizing the reaction: type of lipase, reaction medium, temperature, and ratio of substrates. Finally, this review discusses the latest trends and recent developments, showing the unlimited potential for optimization of such enzymatic syntheses.
... [2][3][4] Despite the growing interest for the synthesis of sugar esters from different sugars, such as glucose, fructose and maltose, very few studies have been reported on lactose. 1,[5][6][7] Lactose is a disaccharide and the main sugar in whey and milk, which can be transformed into value-added products, such as biosurfactants, alcoholic beverages and lactic acid. 8 Lactose monoester derivatives were synthesized in the 1970s for the rst time and received increasing attention due to their potential anticancer activity. ...
... There is a limited number of studies dealing with the potential applications of lactose-based surfactants for pharmaceutical applications. 7,10 According to the World Health Organization statistics, cancer has been known as one of the major causes of death in the world. The traditional therapeutic ways to eliminate cancer cells generate high toxicity. ...
In this study, a lactose fatty acid ester was enzymatically synthesised using immobilized Candida rugosa lipase (CRL). Its anticancer property against K562 leukemia and HeLa cancer cells was carefully investigated. In the first step, a de novo strategy was applied to encapsulate CRL into a microporous zeolite imidazolate framework called ZIF-8. Various characterization techniques including powder X-ray diffraction, Fourier transform infrared spectroscopy, N2 adsorption–desorption, field-emission scanning electron microscopy and thermogravimetric analysis were used to prove the successful encapsulation of CRL molecules during the formation of ZIF-8 crystals with an enzyme loading of 98% of initial CRL. The effect of various factors such as pH and temperature, affecting the enzymatic activity and reusability of the CRL@ZIF-8 composite were assessed against the free enzyme. Additionally, enzyme catalysis parameters, such as Km and Vmax, were also assessed. The obtained biocatalyst showed excellent activity in a wide pH range of 2–9 and a temperature range of 30–60 °C. According to the experimental results, the CRL@ZIF-8 composite maintained about 63% of its initial activity after 6 cycles of use. In the next step, the synthesized catalyst was applied for the synthesis of lactose caprate via enzymatic esterification of lactose with capric acid. Further experiments were performed to obtain the cytotoxicity profile of the new derivative. The growth inhibitory effect of the produced lactose caprate on K562 leukemia and HeLa cancer cells determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed its potential anticancer effects against both cell lines (IC50, 49.6 and 57.2 μg mL⁻¹). Our results indicate that lactose caprate might be a promising candidate for further studies on K562 leukemia and HeLa cancer cells owing to its possible therapeutic usefulness.
... Glycolipids are renewable, and functional non-ionic surfactants, able themselves to self-assemble in lyotropic phases [17][18][19][20]. An increased attention in the pharmaceutical field is currently devoted to these systems since they can act as permeation enhancers, wound healing promoters and active targeting excipient by exploiting the presence of sugar moieties on the surface of nano-sized DDS such as liposomes and niosomes [21][22][23][24][25][26][27][28][29]. In fact, by the interaction between sugar-based nanoparticles and specific sugar receptors present on specific cell membranes it is possible to release the drug payload specifically where needed. ...
... 2C presents the lipases that catalyzed at the 6 -OH-position (Figure 2C)[12].For example, Zaidan et al. used NER-CRL (immobilized from C. rugosa) for the synthesis of 6 -O-lactose caprate (C10), starting from a lactose/capric acid 2:1 molar ratio in acetone [47]. Liang et al. utilized Lipozyme ® TL IM to catalyze the synthesis of different LEs (C6-C18) using lactose and 1:3 molar ratio vinyl esters in THF/pyridine 1:1 [48]. ...
... [12]. For example, Zaidan et al. used NER-CRL (immobilized from C. rugosa) for the synthesis of 6′-O-lactose caprate (C10), starting from a lactose/capric acid 2:1 molar ratio in acetone ...
Glycolipids are biocompatible and biodegradable amphiphilic compounds characterized by a great scientific interest for their potential applications in various technological areas, including pharmaceuticals, cosmetics, agriculture, and food production. This report summarizes the available synthetic methodologies, physicochemical properties, and biological activity of sugar fatty acid ester surfactants, with a particular focus on 6-O-glucose, 6-O-mannose, 6-O-sucrose, and 6′-O-lactose ones. In detail, the synthetic approaches to this class of compounds, such as enzymatic lipase-catalyzed and traditional chemical (e.g., acyl chloride, Steglich, Mitsunobu) esterifications, are reported. Moreover, aspects related to the surface activity of these amphiphiles, such as their ability to decrease surface tension, critical micelle concentration, and emulsifying and foaming ability, are described. Biological applications with a focus on the permeability-enhancing effect across the skin or mucosa, antimicrobial and antifungal activities, as well as antibiofilm properties, are also presented. The information reported here on sugar-based ester surfactants is helpful to broaden the interest and the possible innovative applications of this class of amphiphiles in different technological fields in the future.
... Both saccharose and lactose are recognized as substrates by Novozym 435 in other solvents, as demonstrated elsewhere. 11,14,18,26 Moreover, CALB is active in diverse DESs, including ChCl/U (1:2 mol/mol), for other (trans)esterification-like reactions. 77 To confirm this, the enzyme was incubated in ChCl/U (1:2) (5% w/w water) containing lactose and vinyl palmitate (0.1 M each) for 24 h and then 0.1 M glycerol was added, thus observing the formation of glyceride monopalmitate (see the Supporting Information, Figure S5). ...
Sugar (fatty acid) esters are industrially relevant compounds, with a cumbersome production process due to the solubility issues of the substrates, which forces the use of environmentally unfriendly reaction media. Herein, deep eutectic solvents (DESs) are considered as a promising solution: several literature examples use glucose and different acyl donors to illustrate the efficient synthesis of sugar esters in classic DESs like choline chloride/urea (ChCl/U). However, this paper discloses that when sugars like lactose or other disaccharides are used, enzymes cannot efficiently perform (trans)esterifications in DESs, while the same reaction can proceed in mixtures like pyridine/tetrahydrofuran (Py/THF). This could be explained by computational solubility studies and molecular dynamics simulations of both reaction media, showing two effects: (i) on the one hand, large acyl donors (more than C10) display poor solubility in DESs and (ii) on the other hand, disaccharides interact with DES components. Thus, the DES affects the conformation of lactose (compared to the conformation observed in the Py/THF mixture), in such a way that the enzymatic reaction results impaired. Despite that classic DESs (e.g., ChCl/U) may not be useful for generalizing their use in saccharide ester syntheses, the achieved theoretical understanding of the reaction may enable the design of future DESs that can combine enzyme compatibility with eco-friendliness and efficiency in sugar chemistry.
... Among all of them, sugar-based fatty acid esters are the most common and easy to find on the market due to their many investigated applications. In particular, the emulsifying and permeability-enhancing ability as well as the antimicrobial and antibiofilm properties of lactose-based esters with saturated and unsaturated fatty acid have been described previously by our group [13][14][15][16][17][18][19]. Moreover, we synthesized a series of lactose-based monoesters bearing saturated C10, C12, C14, or C16 acyl chains and evaluated cytotoxicity and the ability to decrease transepithelial electrical resistance (TEER) on airway epithelium Calu-3 cells. ...
The delivery of therapeutics across biological membranes (e.g., mucosal barriers) by avoiding invasive routes (e.g., injection) remains a challenge in the pharmaceutical field. As such, there is the need to discover new compounds that act as drug permeability enhancers with a favorable toxicological profile. A valid alternative is represented by the class of sugar-based ester surfactants. In this study, sucrose and lactose alkyl aromatic and aromatic ester derivatives have been synthesized with the aim to characterize them in terms of their physicochemical properties, structure–property relationship, and cytotoxicity, and to test their ability as permeability enhancer agents across Calu-3 cells. All of the tested surfactants showed no remarkable cytotoxic effect on Calu-3 cells when applied both below and above their critical micelle concentration. Among the explored molecules, lactose p-biphenyl benzoate (URB1420) and sucrose p-phenyl benzoate (URB1481) cause a reversible ~30% decrease in transepithelial electrical resistance (TEER) with the respect to the basal value. The obtained result matches with the increased in vitro permeability coefficients (Papp) calculated for FTIC-dextran across Calu-3 cells in the presence of 4 mM solutions of these surfactants. Overall, this study proposes sucrose- and lactose-based alkyl aromatic and aromatic ester surfactants as novel potential and safe permeation enhancers for pharmaceutical applications.
... In the 2010s, the world production of SFAE was above 6000 tons per year [8] and their market is projected to grow from USD 76 million in 2019 to USD 106 million by 2025 [15]. As part of our ongoing investigations on the synthesis, biological activities, and applications of sugar derivatives [16][17][18][19][20][21][22][23][24], a series of 6-O-sucrose monoesters were designed and synthesized by using an opportunely modified Mitsunobu-type methodology [25] starting from free sucrose and lipophilic acids. This coupling, compared to the others reported in the literature [8,10], such as esterification (acyl chlorides, anhydrides) and transesterification with activated esters (vinyl or enol esters) [26][27][28][29], and/or enzymatic preparation methods [30][31][32], showed higher conversions/yields, high regioselectivity and larger scope including saturated, mono-and polyunsaturated fatty acids or aromatic and alkyl aromatic acids. ...
... After incubation, cell viability was analyzed by the MTT assay. Color development was monitored at 570 nm in a multi-well plate reader (Thermo Scientific, Waltham, MA, USA), and data were expressed as cell viability (%) vs. untreated control Pharmaceuticals 2023, 16,136 15 of 17 cells. The IC 50 value (i.e., the concentration required to reduce cell viability by 50%) was then calculated. ...
... Pharmaceuticals 2023, 16, 136 ...
A small library of 6-O-sucrose monoester surfactants has been synthesized and tested against various microorganisms. The synthetic procedure involved a modified Mitsunobu reaction, which showed improved results compared to those present in the literature (higher yields and larger scope). The antifungal activities of most of these glycolipids were satisfactory. In particular, sucrose palmitoleate (URB1537) showed good activity against Candida albicans ATCC 10231, Fusarium spp., and Aspergillus fumigatus IDRAH01 (MIC value: 16, 32, 64 µg/mL, respectively), and was further characterized through radical scavenging, anti-inflammatory, and biocompatibility tests. URB1537 has been shown to control the inflammatory response and to have a safe profile.
... The use of lactose to produce sugar esters has been scarcely reported to date, [14] despite recent studies have shown the high potential of lactose esters. [15][16][17][18] Galactose-based fatty acid esters have been poorly investigated, too. [14] Lactose is a naturally occurring disaccharide, found in milk, composed of D-galactose and D-glucose. ...
A library of alkyl galactosides was synthesized to provide the “polar head” of sugar fatty acid esters to be tested as non‐ionic surfactants. The enzymatic transglycosylation of lactose resulted in alkyl β‐D‐galactopyranosides, whereas the Fischer glycosylation of galactose afforded isomeric mixtures of α‐ and β‐galactopyranosides and α‐ and β‐galactofuranosides. n‐Butyl galactosides from either routes were enzymatically esterified with palmitic acid, used as the fatty acid “tail” of the surfactant, giving the corresponding n‐butyl 6‐O‐palmitoyl‐galactosides. Measurements of interfacial tension and emulsifying properties of n‐butyl 6‐O‐palmitoyl‐galactosides revealed that the esters of galactopyranosides are superior to those of galactofuranosides, and that the enantiopure n‐butyl 6‐O‐palmitoyl‐β‐D‐galactoside, prepared by the fully enzymatic route, leads to the most stable emulsion. These results pave the way to the use of lactose‐rich cheese whey as raw material for the obtainment of bio‐based surfactants.
... Selected region of the 1 H-NMR spectra (500 MHz, 298 K, MeOD-d 4 ) of compounds 1-6 showing the major anomeric resonances; Figure S3. Modes of action of antimicrobial activity of sugar fatty acid esters [27,42,64,65,69,70,75,[80][81][82][83][84]; Table S1. Zones of inhibition of lauroyl and stearoyl monoesters of sugars reported in the literature since 2018. ...
Forestry and agricultural industries constitute highly relevant economic activities globally. They generate large amounts of residues rich in lignocellulose that have the potential to be valorized and used in different industrial processes. Producing renewable fuels and high-value-added compounds from lignocellulosic biomass is a key aspect of sustainable strategies and is central to the biorefinery concept. In this study, the use of biomass-derived monosaccharides for the enzymatic synthesis of sugar fatty acid esters (SFAEs) with antimicrobial activity was investigated to valorize these agro-industrial residues. With the aim to evaluate if lignocellulosic monosaccharides could be substrates for the synthesis of SFAEs, d-xylose, l-arabinose, and d-glucose, lauroyl and stearoyl monoesters were synthetized by transesterification reactions catalyzed by Lipozyme RM IM as biocatalyst. The reactions were performed using commercial d-xylose, l-arabinose, and d-glucose separately as substrates, and a 74:13:13 mixture of these sugars. The proportion of monosaccharides in the latter mixture corresponds to the composition found in hemicellulose from sugarcane bagasse and switchgrass, as previously described in the literature. Products were characterized using nuclear magnetic resonance (NMR) spectroscopy and showed that only the primary hydroxyl group of these monosaccharides is involved in the esterification reaction. Antimicrobial activity assay using several microorganisms showed that 5-O-lauroyl-d-xylofuranose and 5-O-lauroyl-l-arabinofuranose have the ability to inhibit the growth of Gram-positive bacteria separately and in the products mix. Furthermore, 5-O-lauroyl-l-arabinofuranose was the only product that exhibited activity against Candida albicans yeast, and the four tested filamentous fungi. These results suggest that sugar fatty acid esters obtained from sustainable and renewable resources and produced by green methods are promising antimicrobial agents.
... As a demonstration of this, for their realization, although traditional synthetic chemistry is still used in some cases (e.g., reactions with aromatic or polyunsaturated fatty acids), synthetic methodologies based on enzymes are increasing more and more because they offer the advantage of soft reaction conditions and allow high yields with regioselectivity. In this field of research, in recent years, the studies on glycolipids with lactose as their sugar portion have increased [3,4]. In particular, lactose-based esters with saturated and unsaturated fatty acid, alkyl aromatic and aromatic tails were reported together with their emulsifying, biocompatibility, safety, permeabilityenhancing, antimicrobial and antibiofilm properties [5][6][7][8][9]. ...
... Lactose monohydrate was purchased from Carlo Erba (Milan, Italy). Undecylenic acid, Lipozyme ® (immobilized lipase from Mucor miehei), tetrafluoroboric acid diethyl ether complex (HBF 4 . Et 2 O), acetonitrile (CH 3 CN), ethyl acetate (EtOAc), methanol (MeOH), toluene, and deuterated solvents chloroform (CDCl 3 ) and dimethylsulfoxide (DMSO-d6) were purchased from Sigma-Aldrich (Milan, Italy). ...
As a follow-up to our previous studies on glycolipid surfactants, a new molecule, that is lactose 6′-O-undecylenate (URB1418), was investigated. To this end, a practical synthesis and studies aimed at exploring its specific properties were carried out. URB1418 showed antifungal activities against Trichophyton rubrum F2 and Candida albicans ATCC 10231 (MIC 512 μg/mL) and no significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. At the same time, it presented anti-inflammatory properties, as documented by the dose-dependent reduction in LPS-induced NO release in RAW 264.7 cells, while a low antioxidant capacity in the range of concentrations tested (EC50 > 200 µM) was also observed. Moreover, URB1418 offers the advantage of being more stable than the reference polyunsaturated lactose esters and of being synthesized using a “green” procedure, involving an enzymatic method, high yield and low manufacturing cost. For all these reasons and the absence of toxicity (HaCaT cells), the new glycolipid presented herein could be considered an interesting compound for applications in various fields.
