Carbohydrate‑functionalized liposomes are promising drug‑delivery systems due to their biocompatibility, biodegradability, low toxicity, and ability to mediate targeted cell interactions. However, conventional functionalization strategies rely on multi‑step chemical conjugations that introduce variability, hinder large‑scale production, and compromise formulation stability. Here, we overcome these limitations by achieving liposome functionalization without surface chemistry. We introduce "sweetosomes," a newly formulated class of sugar‑decorated liposomes designed for cancer targeting, which promote more specific and active cellular uptake, prolonged intracellular retention, and enhanced endosomal escape. We show that organelle acidity can be selectively modulated by fucosylated sweetosomes, supporting their role in facilitating endosomal escape an essential step for the cytoplasmic delivery of biological therapeutics. Fucosylated sweetosomes and blank liposomes enter cells but traffic through distinct endosomal pathways; indeed, fucose residues appear to alter endosomal maturation and function. Our findings validate fucosylated sweetosomes as optimized lipid nanostructures for intestinal cancer targeting, demonstrating significantly improved curcumin delivery, primarily via the caveolae pathway. Finally, fucosylated sweetosomes highlight translational potential, due to their prolonged plasma persistence, as detected by ex vivo plasma and blood‑cell analyses.

A protecting-group-free Mizoroki-Heck arylation of olefins with N-unprotected bromobisindole ethanamines and, more generally, N-unprotected heterocyclic electrophiles is described. Efficient palladium-catalyzed coupling is achieved through appropriate base selection: CsF is optimal for substrates bearing intrinsic basic sites, whereas 1-decylamine is required. The method tolerates a wide range of styrenes, heteroaryl olefins, acrylates, and N-containing substrates, including unprotected tryptamines, anilines, and haloindole derivatives. Its practicality is also demonstrated by the synthesis of the natural product trans-resveratrol.

Leishmaniasis is a neglected tropical disease which presents significant global health challenges due to the lack of effective vaccines and the limitations of existing chemotherapeutics in view of their toxicity, resistance, and high costs. In this study, we realized a library of novel bisindole derivatives as potential antileishmanial agents through a rapid Suzuki-Miyaura coupling reaction, utilizing NH2-unprotected bromobisindole ethanamines and boronic acids. Optimization of reaction conditions allowed for the efficient and selective arylation of these substrates, with yields up to 93%. The compounds were screened for their activity against Leishmania infantum promastigotes. Among the tested bisindole derivatives, 3af (bearing a 4-vinylphenyl moiety) demonstrated potent antileishmanial activity (IC50 = 1.1 µM) with a higher selectivity index (21.8) compared to the reference drug miltefosine (9.8). A significant activity was also retained against intracellular amastigotes. This study establishes a robust methodology for late-stage functionalization of bisindoles, also highlighting these derivatives' potential as promising leads for antileishmanial drug development.

Cinnamic Acid Sugar Ester Derivatives (CASEDs) are a class of natural compounds that exhibit several interesting biological activities. However, to date, no examples of their use in sunscreen formulations have been reported. Here, we describe the synthesis of a series of novel cinnamic acid esters of glucose (4a-g), ribose (4h) and lactose (4i) starting from the respective acetals 3. The latter were obtained through oxidative alkoxycarbonylation of olefins. For all compounds 3 and 4, UV-Vis spectra were recorded and lipophilicity (i.e., clogP) and cytotoxicity were evaluated. All but one of the synthesized compounds were found to be non-cytotoxic at the concentrations tested and, as expected, absorption spectra depended only on the substituents on the aromatic ring. Finally, the ad hoc synthesized compound 3k, featuring a 4-methoxy substituent on the phenyl ring and a 1,2-O-isopropylidene ribose moiety, provided the most promising results for a possible use as a sunscreen. Indeed, its Sun Protection Factor (SPF), calculated in vitro, was higher with respect to that of ethylhexyl methoxycinnamate (EHMC), which is already utilized in sun care products. Moreover, 3k showed greater antioxidant properties than EHMC, effectively protecting keratinocytes against H2O2-induced oxidative damage. At the same time, it showed no cytotoxic effects and preserved cellular metabolic activity and protein content. Based on these results, we believe that CASEDs could find valid applications in the skincare and cosmetics sectors.

N-Acyl amino acids are biodegradable anionic amphiphilic molecules made up of linear fatty acids as hydrophobic tails and amino acids as polar heads, which are promising for their applicability in different technological fields. In the light of widening their use, a deeper understanding of their interactions with biological membranes is required, especially to further assess their toxicological profile. We investigated the interaction between N-decanoyl amino acid surfactants and phospholipid bilayers as simple in vitro models for biological membranes in comparison to sodium dodecyl sulfate using neutron scattering techniques. The information from small angle neutron scattering (SANS, q range from 0.008 to 0.25 Å-1) focusing on liposome-to-surfactant interactions and neutron reflectivity (NR, Q range measured at three incident angles θ = 0.35, 0.65, and 1.5°) focusing on lipid bilayer-to-surfactant interactions was combined to provide a detailed characterization. All amino acid surfactants (C10-alanine, C10-glycine, C10-leucine, C10-methionine, C10-serine, and C10-proline) exhibited a similar behavior in terms of incorporation in liposomes and lipid removal as well as adsorption profiles in bilayers up to their critical micelle concentration (CMC). Notably, bilayer destabilization occurred for all surfactants (except for C10-serine and C10-alanine) at a concentration between CMC and 2× CMC. Such a result demonstrates the exceptional ability of C10-serine and C10-alanine to integrate into bilayers without disruption up to concentrations as high as ∼3-4× CMC. These findings support the lower cytotoxic effect of C10-serine and C10-alanine surfactants, observed in previous studies, and provide new insights on the mechanism of interaction of N-decanoyl amino acids with lipid membranes.

A chemoselective one-pot synthesis of indole–pyrrole hybrids has been developed. The new hybrids were phenotypically screened for efficacy against L. infantum promastigotes. Compound 3d was the most active with IC50 = 9.6 μM and a selectivity index of 5.

Carbonylation reactions carried out at room temperature and at atmospheric pressure of carbon monoxide are highly attractive and extremely rare at the same time. Here, the oxidative alkoxycarbonylation of styrenes to industrially relevant cinnamates has been developed under such a mild conditions (rt, 1 atm of CO) in the presence of a palladium(II) complex bearing a bis(aryl)acenaphthenequinonediimine ligand, benzoquinone and p-toluenesulfonic acid. Remarkably, variously substituted styrene derivatives have been efficiently carbonylated using a nearly stoichiometric amount of alcohols, with a dramatic reduction of waste. Even reluctant internal alkenes have shown to be compatible under these carbonylative conditions. In consideration of experimental results and DFT calculations a mechanistic rationale has been proposed. Based on this study, the benzoquinone has been found to promote the final palladium reoxidation, and to boost the reaction under such unprecedent mild conditions. The present methodology has been successfully exploited for the synthesis of high value-added cinnamoyl glycerols and cinnamic acid sugar esters, including the 6-O-p-coumaroyl-D-glucose natural product.

Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary in vivo test. The novel bisindoles were phenotypically screened for efficacy against Leishmania infantum promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC50 below 10 μM. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC50 = 2.7 μM) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC50 of 11.1 and 6.8 μM for 1h and 2c, respectively. Moreover, 1h showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, 1h could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.

Indole-3-carbinol (I3C) is a natural product contained in vegetables belonging to the Brassicaceae family and has been studied in recent decades for its biological and pharmacological properties. Herein, we will analyze: (1) the biosynthetic processes and synthetic procedures through which I3C and its main derivatives have been obtained; (2) the characteristics that lead to believe that both I3C and its derivatives are responsible for several important activities-in particular, antitumor and antiviral, through insights concerning in vitro assays and in vivo tests; (3) the mechanisms of action of the most important compounds considered; (4) the potential social impact that the enhancement of the discussed molecules can have in the prevention and treatment of the pathologies' examined field-first of all, those related to respiratory tract disorders and cancer.

Lyotropic Liquid Crystalline (LLC) nanoparticles represent an emerging class of smart, biocompatible, and biodegradable systems for the delivery of drugs. Among these, structures with complex 3D architectures such as cubosomes are of particular interest. These are non- lamellar assemblies having hydrophobic and hydrophilic portions able to carry drugs of different nature. They can further be modulated including suitable additives to control the release of the active payload, and to promote an active targeting. Starting from monoolein (GMO) cubic phase, different concentrations of mannose-based esters were added, and the eventual structural modifications were monitored to ascertain the effects of the presence of glycolipids. Moreover, the structural properties of these nanosystems loaded with Dexamethasone (DEX), a very well-known anti-inflammatory steroid, were also studied. Experiments were carried out by synchrotron Small Angle X-ray Scattering (SAXS), Raman Microspectroscopy (RMS) and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) measurements. The drug delivery potential (i.e. entrapment efficiency and release properties) of the obtained nanoparticles was evaluated. Finally, in vitro cytocompatibility and anti-inflammatory activity studies of the prepared formulations were carried out. Inclusion of mannose-based surfactants up to 10 mol% influenced the structural parameters of Im3m cubic phase and swollen cubic phases were obtained with the different glycolipids with lattice parameters significantly higher than GMO. A complete cytocompatibility and an increased DEX activity were observed, thus suggesting the possibility to use GMO/glycolipids nanoparticles to formulate innovative drug delivery systems.

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.

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.

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.

ChiralityVolume 34, Issue 12 p. 1491-1493 EDITORIAL Special issue: Chirality in pharmaceutical research and development Simona Collina, Simona Collina University of Pavia, Pavia, ItalySearch for more papers by this authorSimone Lucarini, Simone Lucarini Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, ItalySearch for more papers by this authorJordi Benet-Buchholz, Jordi Benet-Buchholz Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona, SpainSearch for more papers by this authorOliver Trapp, Oliver Trapp University of Munich, Munich, GermanySearch for more papers by this authorGennaro Pescitelli, Gennaro Pescitelli University of Pisa, Pisa, ItalySearch for more papers by this authorNina Berova, Nina Berova Columbia University, New York, New York, USASearch for more papers by this author Simona Collina, Simona Collina University of Pavia, Pavia, ItalySearch for more papers by this authorSimone Lucarini, Simone Lucarini Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, ItalySearch for more papers by this authorJordi Benet-Buchholz, Jordi Benet-Buchholz Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona, SpainSearch for more papers by this authorOliver Trapp, Oliver Trapp University of Munich, Munich, GermanySearch for more papers by this authorGennaro Pescitelli, Gennaro Pescitelli University of Pisa, Pisa, ItalySearch for more papers by this authorNina Berova, Nina Berova Columbia University, New York, New York, USASearch for more papers by this author First published: 27 October 2022 https://doi.org/10.1002/chir.23510 [This article is part of the Special issue: Chirality in Pharmaceutical Research and Development. See the first articles for this special issue previously published in Volumes 34:3, 34:6, 34:7, 34:8, 34:9, 34:10, and 34:11. More special articles will be found in this issue as well as in those to come.] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume34, Issue12December 2022Pages 1491-1493 This article also appears in:Chirality in Pharmaceutical Research and Development RelatedInformation

In recent years, researchers are exploring innovative green materials fabricated from renewable natural sub-stances to meet formulation needs. Among them, biopolymers like chitosans and biosurfactants such as sugar fatty acid esters are of potential interest due to their biocompatibility, biodegradability, functionality, and cost-effectiveness. Both classes of biocompounds possess the ability to be efficiently employed in wound dressing to help physiological wound healing, which is a bioprocess involving uncontrolled oxidative damage and inflam-mation, with an associated high risk of infection. In this work, we synthesized two different sugar esters (i.e., lactose linoleate and lactose linolenate) that, in combination with chitosan and sucrose laurate, were evaluated in vitro for their cytocompatibility, anti-inflammatory, antioxidant, and antibacterial activities and in vivo as wound care agents. Emphasis on Wnt/beta-catenin associated machineries was also set. The newly designed lactose esters, sucrose ester, and chitosan possessed sole biological attributes, entailing considerable blending for convenient formulation of wound care products. In particular, the mixture composed of sucrose laurate (200 mu M), lactose linoleate (100 mu M), and chitosan (1%) assured its superiority in terms of efficient wound healing prospects in vivo together with the restoring of the Wnt/beta-catenin signaling pathway, compared with the marketed wound healing product (Healosol (R)), and single components as well. This innovative combination of biomaterials applied as wound dressing could effectively break new ground in skin wound care.

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.

Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis, affect billions of people and are responsible for almost 500,000 deaths/year. In particular, leishmaniasis, a neglected tropical disease, is considered a global public health problem because current drugs have several drawbacks including to toxicity, high cost, and drug resistance, which result in a lack of effective and readily available therapies. Therefore, the synthesis of new, safe, and effective molecules still requires the attention of the scientific community. Moreover, it is well known that chirality plays a crucial role in the antiparasitic activity of molecules, driving the design of their synthesis. Therefore, in this review we report a recent update on new chiral compounds with promising antileishmanial activity, focusing on synthetic approaches. Where reported, in most cases the enantiopure compound has shown better potency against the protozoa than its enantiomer or corresponding racemic mixture.

2,2-bis(6-bromo-1H-indol-3-yl) ethanamine, a marine bisindole alkaloid, showed anticancer property in several tumor cell lines thanks to the presence of a 3,3'-diindolylmethane scaffold. Here, the modifications in its chemical structure into alkaloid-like derivatives, have been evaluated, to investigate changes in its biological activities. Three derivatives have been considered and their potential apoptotic action has been evaluated through morpho-functional analyses in a human cancer cell line. Apoptosis appears strongly decreased in the derivatives without the bromine atoms (1) and in those where the bromine atoms have been substituted with fluorine atoms (2). On the contrary, the methylation of indole NH (3) does not alter the alkaloid apoptotic activity that occurs through mitochondria involvement supported by cardiolipin peroxidation and dysfunctional mitochondria presence. This manuscript highlights the alkaloid derivative cytotoxic effect, which is strictly correlated to the presence of N-methylated bisindole alkaloid and bromine atoms, conditions which assure to maintain the pro-apoptotic activity. Since molecular therapies, by targeting mitochondria pathways, have shown positive outcomes against several cancer cells, the alkaloid with bisindole methylated scaffold and the two bromine atoms can be considered a promising candidate to develop new derivatives with strong anticancer property. RESEARCH HIGHLIGHTS: 2,2-bis(6-bromo-1H-indol-3-yl) ethanamine is an alkaloid known for its anticancer properties. Morpho-functional analyses evaluated cytotoxicity of its synthetic derivatives in tumor cells. Anticancer properties depend on the presence of bisindole scaffold and the two bromine units.

In crystal structures of melatonin MT1 and MT2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT2 receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket. Thermodynamic integration simulations applied to MT1 and MT2 receptors in complex with the α-naphthyl derivative provided a rationale for the MT2-selectivity and investigation on the binding mode of a couple of atropisomers allowed to define the available space and arrangement of substituents inside the subpocket. Interestingly, more hydrophilic 2-aza-substituted compounds displayed high binding affinity and molecular dynamics simulations highlighted polar interaction with residues from the subpocket that could be responsible for their potency.

We report the evaluation of a small library of azole-bisindoles for their antileishmanial potential, in terms of efficacy on Leishmania infantum promastigotes and intracellular amastigotes. Nine compounds showed good activity on L. infantum MHOM/TN/80/IPT1 promastigotes with IC50 values ranging from 4 to 10 μM. These active compounds were also tested on human (THP-1, HEPG2, HaCaT, and human primary fibroblasts) and canine (DH82) cell lines. URB1483 was selected as the best compound, with no quantifiable cytotoxicity in mammalian cells, to test the efficacy on intracellular amastigotes. URB1483 significantly reduced the infection index of both human and canine macrophages with an effect comparable to the clinically used drug pentamidine. URB1483 emerges as a new anti-infective agent with remarkable antileishmanial activity and no cytotoxic effects on human and canine cells.