Lauroyl Groups Research Articles

Lauroylated Histidine-Enriched S413-PV Peptide as an Efficient Gene Silencing Mediator in Cancer Cells.

This study aimed to endow the cell-penetrating peptide (CPP) S413-PV with adequate features towards a safe and effective application in cancer gene therapy. Peptide/siRNA complexes were prepared with two new derivatives of the CPP S413-PV, which combine a lauroyl group attached to the N- or C-terminus with a histidine-enrichment in the N-terminus of the S413-PV peptide, being named C12-H5-S413-PV and H5-S413-PV-C12, respectively. Physicochemical characterization of siRNA complexes was performed and their cytotoxicity and efficiency to mediate siRNA delivery and gene silencing in cancer cells were assessed in the absence and presence of serum. Peptide/siRNA complexes prepared with the C12-H5-S413-PV derivative showed a nanoscale (ca. 100nm) particle size, as revealed by TEM, and efficiently mediated gene silencing (37%) in human U87 glioblastoma cells in the presence of 30% serum. In addition, the new C12-H5-S413-PV-based siRNA delivery system efficiently downregulated stearoyl-CoA desaturase-1, a key-enzyme of lipid metabolism overexpressed in cancer, which resulted in a significant decrease in the viability of U87 cells. Importantly, these complexes were able to spare healthy human astrocytes. These encouraging results pave the way for a potential application of the C12-H5-S413-PV peptide as a promising tool in cancer gene therapy.

Synthesis of novel cellulose mixesters for transparent responsive films with switchable mechanical properties

Soft actuators have attracted much attention during the last decades due to their potentially broad applications ranging from sensors to artificial muscles. Up to now, most of such soft actuators are still based on synthetic polymers. Herein, we described a novel group of materials derived from sustainable cellulose as potential starting materials for the preparation of soft actuators. To be precisely, cellulose mixesters with acyl esters of distinct chain lengths and cinnamic ester were synthesized through a two-step synthesis and used for the preparation of responsive thin film actuators. These cellulose mixesters have degree of substitution ascribed to stearoyl groups (DSSt) of 1.51 or lauroyl groups (DSLa) of 1.48 and degree of substitution ascribed to cinnamoyl groups (DSCi) around 1.35. Furthermore, the influence of the chain lengths of the two different aliphatic esters as well as the switchable crosslinking of cinnamoyl moieties on the materials properties was further shown. Using these cellulose mixesters, transparent thin films with thickness of 4−15 μm were prepared via facile solvent casting. These films had light-responsive mechanical properties from rigid to elastic after illumination with UV light of distinct wavelengths (254 nm and 310−400 nm). Moreover, the thin films showed shape memory effect and the ability of self-healing.

PASS Predication, Antiviral, in vitro Antimicrobial, and ADMET Studies of Rhamnopyranoside Esters

Sugar derived esters (SEs) with potential antimicrobial activity were found to be a better choice to solve the multidrug resistant (MDR) pathogens due to improved antimicrobial efficacy, biodegradability, non-toxic, and non-allergic properties. In this context, a series of benzyl a-L-rhamnopyranoside esters with different chain length (C2-C18) were employed for PASS predication, antiviral, and in vitro antimicrobial activity test. The in vitro antimicrobial tests against four bacterial, and four fungal pathogens along with PASS predication indicated that these sugar esters acted as better antifungals as compared to antibacterial functionality. The study revealed that the incorporation of octanoyl (C8) and lauroyl (C12) group(s) at C-3 position of rhamnopyranoside possessed promising antimicrobial, and anti-carcinogenic potentiality with good pharmacokinetic (pkCSM), and drug likeness properties. Also, attachment of multiple ester groups enhanced various drug likeness, and medicinal chemistry friendliness conditions. Overall, the present findings might be useful for the development of rhamnopyranoside based novel MDR antimicrobial drugs.

Preparation of superhydrophobic polyimide microstructural layer on copper mesh for oil/water separation

With the development of economy and society, the wanton chaotic emission of oily wastewater causes serious pollution to environment. We attempt to prepare the superhydrophobic copper meshes modified by hierarchical polymeric microstructures to separate oil/water mixtures. After a solvothermal process and an acylation reaction, the surface of copper meshes can be well coated with a polyimide layer modified by lauroyl groups. The obtained meshes exhibited both superhydrophobic and superoleophilic properties with a water contact angle above 150° due to the increased roughness and the hydrophobic property of long alkyl chains. Moreover, the modified meshes exhibit good durability under strongly acidic and alkaline environment conditions. Thereby, the as-prepared meshes can act as a high performance filter to separate oil/water mixture with a good reusability. It is expected that the superhydrophobic surface can serve as a promising alternative to conventional techniques for oil/water separation.

Antimicrobial activity of linear lipopeptides derived from BP100 towards plant pathogens.

A collection of 36 lipopeptides were designed from the cecropin A-melittin hybrid peptide BP100 (H-Lys-Lys-Leu-Phe-Lys-Lys-Ile-Leu-Lys-Tyr-Leu-NH2) previously described with activity against phytopathogenic bacteria. These lipopeptides were synthesized on solid-phase and screened for their antimicrobial activity, toxicity and proteolytic stability. They incorporated a butanoyl, a hexanoyl or a lauroyl group at the N-terminus or at the side chain of a lysine residue placed at each position of the sequence. Their antimicrobial activity and hemolysis depended on the fatty acid length and its position. In particular, lipopeptides containing a butanoyl or a hexanoyl chain exhibited the best biological activity profile. In addition, we observed that the incorporation of the acyl group did not induce the overexpression of defense-related genes in tomato. Best lipopeptides were BP370, BP378, BP381, BP387 and BP389, which were highly active against all the pathogens tested (minimum inhibitory concentration of 0.8 to 12.5 μM), low hemolytic, low phytotoxic and significantly stable to protease degradation. This family of lipopeptides might be promising functional peptides useful for plant protection.

Synthesis of novel and regioselectively mesogen-incorporated thermotropic liquid crystals from cellulose derivatives

ABSTRACTRegioselectively mesogen-incorporated cellulose derivatives, in which the hydroxy group at C-6 is displaced by a bulky and rigid mesogenic group such as {4-[(4-methoxyphenoxy)carbonyl]phenoxy}acetate or [(4′-cyanobiphenyl-4-yl)oxy]acetate, and the C-2 and C-3 groups are displaced by octanoyl or lauroyl groups, were synthesized. Thermogravimetric and differential scanning calorimetric analyses of the final products, along with polarized optical microscopic observations, revealed that the obtained cellulose derivatives have a thermotropic liquid-crystalline nature and transition from the mesomorphic to the isotropic phase over a wide range of temperatures. These derivatives could be considered to be main-chain liquid-crystalline cellulosic polymers.

Use of dodecanoyl isothiocyanate as building block in synthesis of target benzothiazine, quinazoline, benzothiazole and thiourea derivatives

AbstractDodecanoyl isothiocyanate (

Semisynthesis and in vitro cytotoxic evaluation of new analogues of 1-O-acetylbritannilactone, a sesquiterpene from Inula britannica

Semisynthetic analogues of the natural product 1-O-acetylbritannilactone (ABL), a sesquiterpene isolated from the medicinal plant Inula britannica, have been prepared and exhibited significant in vitro cytotoxic activities against four cell lines including three human cancer cell lines (HCT116, HEp-2 and HeLa) and one normal hamster cell line (CHO). Structure–activity relationships indicate that esterification of 6-OH (enhanced lipophilicity) and α-methylene-γ-lactone functionalities play important roles in conferring cytotoxicity. Among the tested compounds, 14 bearing a lauroyl group (12C) at the 6-OH position displayed most potent in vitro cytotoxic activity, with IC50 values between 2.91 and 6.78 μM, comparable to the positive control etoposide (VP-16, IC50 values between 2.13 and 4.79 μM). Moreover, the compound 14 triggered remarkable apoptosis at a low concentration, and induced cell cycle arrest in G2/M phase in HCT116 cells. The biological assays conducted with normal cells (CHO) revealed that all the synthetic compounds are no selective against cancer cell lines tested.

Deletion of the β-Acetoacetyl Synthase FabY in Pseudomonas aeruginosa Induces Hypoacylation of Lipopolysaccharide and Increases Antimicrobial Susceptibility

The β-acetoacetyl-acyl carrier protein synthase FabY is a key enzyme in the initiation of fatty acid biosynthesis in Pseudomonas aeruginosa. Deletion of fabY results in an increased susceptibility of P. aeruginosa in vitro to a number of antibiotics, including vancomycin and cephalosporins. Because antibiotic susceptibility can be influenced by changes in membrane lipid composition, we determined the total fatty acid profile of the ΔfabY mutant, which suggested alterations in the lipid A region of the lipopolysaccharide. The majority of lipid A species in the ΔfabY mutant lacked a single secondary lauroyl group, resulting in hypoacylated lipid A. Adding exogenous fatty acids to the growth media restored the wild-type antibiotic susceptibility profile and the wild-type lipid A fatty acid profile. We suggest that incorporation of hypoacylated lipid A species into the outer membrane contributes to the shift in the antibiotic susceptibility profile of the ΔfabY mutant.

N-lauroyl chitosan surface-modified PLGA nanoparticles as carrier for adriamycin to overcome cancer drug resistance

N-lauroyl chitosan (NLCS) conjugates with different degrees of substitution (DS) of lauroyl group were synthesized and used to prepare surface modified poly(lactic-co-glycolic) acid (NLCS-PLGA) nanoparticles via hydrophobic interaction and ionic bond force. NLCS-PLGA nanoparticles had spherical shape with shell-core structure and exhibited the smallest size and narrowest size distribution when DS of lauroyl group of NLCS was 8.5%. Adriamycin (ADR), as a model antitumor drug, was loaded into NLCS-PLGA nanoaprticles and its initial burst release from PLGA nanoparticles was significantly reduced. MTT assay showed that NLCS-2-PLGA nanoaprticles evidently enhanced cytotoxicity of ADR against drug-resistant breast cancer MCF-7/ADR cells, both compared to free ADR and ADR-loaded PLGA nanoparticles. Moreover, cell-live images showed that the cellular uptake and nuclear location of ADR in MCF-7/ADR cells were significantly enhanced by loading of NLCS-2-PLGA nanoparticles. In conclusion, this novel carrier of anticancer drugs has the potential to overcome drug resistance in cancer cells.

Lycorine Derivatives Against Trichomonas vaginalis

Six lycorine derivatives were prepared, characterized, and evaluated for their in vitro anti-Trichomonas vaginalis activity. Compounds bearing an acetyl (2), lauroyl (3), benzoyl (4 and 5), and p-nitrobenzoyl (6 and 7) groups were synthesized. The best activity was achieved with lycorine esterified at C-2 position with lauroyl group. Preliminary structure-activity relationship points that unprotected OH group at C-1 and C-2 is not necessary to the antiparasitic activity, and none of the derivative was less active than lycorine. The lycorine structural requisites required to kill this amitochondriate cell seem to be different in comparison with the derivatives most active against other parasites and tumor cell lines, both mitochondriated cells. This result is an important contribution with our ongoing studies regarding the mechanism of action of the Amaryllidaceae alkaloids on T.vaginalis cell death opening a new perspective to optimize this innovative pharmacological potential.

Preparation of Long-Chain Fatty Acyl-Grafted Chitosan in an Ionic Liquid and Their Self-Assembled Micelles in Water

Controllable synthesis of self-associating lauroyl-grafted chitosan with high molecular weight was realized in ionic liquid reacting media. The obtained lauroyl chitosan with different grafting degrees was characterized by FT-IR and 1H-NMR spectra. The chitosan derivatives were able to self-assemble into spherical polymeric micelles in water. The onset of micellization or critical micelle concentration (CMC) was estimated by fluorescence spectroscopy. The hydrodynamic diameters of various lauroyl chitosan micelles, determined by dynamic light scattering, were in the range of 122–295 nm. The morphology of the micelles was observed by scanning electron microscopy. The self-assembly behavior and the size of the assembled micelles of lauroyl chitosan were affected by the grafting degree of lauroyl groups. Generally, higher grafting degree resulted in lower CMC and smaller micelle size. These lauroyl chitosan nano-micelles may have potential applications in biological and medical fields.

Development of lauroyl sulfated chitosan for enhancing hemocompatibility of chitosan

Chitosan (CS) has received much attention as a functional biopolymer especially in pharmaceutical applications, but has serious limitations owing to its poor hemo-compatibility property. Present paper focuses on the chemical modification of CS in order to enhance hemocompatibility. Amphiphilic derivative (lauroyl sulfated chitosan, LSCS) was prepared by the inclusion of sulfo group (hydrophilic) and lauroyl group (hydrophobic) to CS backbone and particles were prepared by an ionic-gellation approach. Modification was confirmed by FTIR, NMR and zeta potential measurements and the microparticles were evaluated for its particle size, swelling properties and thermal behaviour. Blood compatibility studies like hemolysis, RBC, WBC, platelet aggregation studies, blood clotting time, protein adsorption and C3 protein depletion assay were carried out for these polymers using standard techniques and cytotoxicity studies were performed to understand its applicability. Negatively charged (-6.06 mV) LSCS submicroparticles (886 nm) were prepared in this study. Blood compatibility studies demonstrated that the amphiphilic modification improved the hemocompatibility of CS. RBC aggregation and hemolysis induced by CS were significantly reduced by this modification. Further amphiphilic modification was effective in reducing the protein adsorption on CS. LSCS derivatives were found to be non-toxic in L929 cell lines. From these studies, it appears that LSCS is a hemocompatible version of CS.

Enhanced cellular uptake and metabolic stability of lipo‐oligoarginine peptides

Developing efficient cellular delivery vectors is crucial for designing novel therapeutic agents to enhance their plasma membrane permeability and metabolic stability in cells. Previously, we engineered cell penetrating peptide vectors named as "lipo-oligoarginine peptides" (LOAPs) by conjugating a proper combination of fatty acid and oligoarginine that translocated into cell easily without adverse effect on cell viability. In the present study, we report a systemic evaluation of cellular uptake and metabolic stability of LOAPs in Jurkat cells by introducing different combination of D-Arg residues in the peptide backbone. The cellular uptake and intracellular fate, cell viability, and metabolic stability and proteolytic degradation patterns of various LOAPs consisted of different combination of L- and D-Arg sequences were confirmed by flow cytometry, cytotoxicity assay, and analytical RP-HPLC with MALDI-TOF mass. All investigated LOAPs penetrated the cell efficiently with low cellular toxicity. The LOAPs having D-Arg residues at their N-termini seemed to have better metabolic stability than the LOAPs having C-terminal D-Arg residues. The metabolic degradation patterns were similar among all investigated LOAPs. The major hydrolytic site was between lauroyl group and β-Ala residue. Without the lipid chain, the oligoarginine peptide was pumped out ofcells easily. The results presented in this study suggest that structurally modified LOAPs could be used as a novel CPP design toward improved therapeutic application.

Controllable inhibition of cellular uptake of oxidized low-density lipoprotein: Structure–function relationships for nanoscale amphiphilic polymers

A family of anionic nanoscale polymers based on amphiphilic macromolecules (AMs) was developed for controlled inhibition of highly oxidized low-density lipoprotein (hoxLDL) uptake by inflammatory macrophage cells, a process that triggers the escalation of a chronic arterial disease called atherosclerosis. The basic AM structure is composed of a hydrophobic portion formed from a mucic acid sugar backbone modified at the four hydroxyls with lauroyl groups conjugated to hydrophilic poly(ethylene glycol) (PEG). The AM structure-activity relationships were probed by synthesizing AMs with six key variables: length of the PEG chain, carboxylic acid location, type of anionic charge, number of anionic charges, rotational motion of the anionic group, and PEG architecture. All AM structures were confirmed by nuclear magnetic resonance spectroscopy and their ability to inhibit hoxLDL uptake in THP-1 human macrophage cells was compared in the absence and presence of serum. We report that AMs with one, rotationally restricted carboxylic acid within the hydrophobic portion of the polymer was sufficient to yield the most effective AM for inhibiting hoxLDL internalization by THP-1 human macrophage cells under serum-containing conditions. Further, increasing the number of charges and altering the PEG architecture in an effort to increase serum stabilization did not significantly impair the ability of AMs to inhibit hoxLDL internalization, suggesting that selected modifications to the AMs could potentially promote multifunctional characteristics of these nanoscale macromolecules.

PapA3 Is an Acyltransferase Required for Polyacyltrehalose Biosynthesis in Mycobacterium tuberculosis

Mycobacterium tuberculosis possesses an unusual cell wall that is replete with virulence-enhancing lipids. One cell wall molecule unique to pathogenic M. tuberculosis is polyacyltrehalose (PAT), a pentaacylated, trehalose-based glycolipid. Little is known about the biosynthesis of PAT, although its biosynthetic gene cluster has been identified and found to resemble that of the better studied M. tuberculosis cell wall component sulfolipid-1. In this study, we sought to elucidate the function of papA3, a gene from the PAT locus encoding a putative acyltransferase. To determine whether PapA3 participates in PAT assembly, we expressed the protein heterologously and evaluated its acyltransferase activity in vitro. The purified enzyme catalyzed the sequential esterification of trehalose with two palmitoyl groups, generating a diacylated product similar to the 2,3-diacyltrehalose glycolipids of M. tuberculosis. Notably, PapA3 was selective for trehalose; no activity was observed with other structurally related disaccharides. Disruption of the papA3 gene from M. tuberculosis resulted in the loss of PAT from bacterial lipid extracts. Complementation of the mutant strain restored PAT production, demonstrating that PapA3 is essential for the biosynthesis of this glycolipid in vivo. Furthermore, we determined that the PAT biosynthetic machinery has no cross-talk with that for sulfolipid-1 despite their related structures.

Synthesis and immunological evaluation of self-adjuvanting glycolipopeptide vaccine candidates

Synthesis of four glycolipids with different number of lauroyl groups on glucose or cellobiose as scaffolds is described. Their immunological evaluations either admixed with or covalently linked to J8, a peptide antigen derived from the C-terminus of the antiphagocytic M-protein of group A streptococcus, are also investigated. Administration of mixtures of J8 and glycolipids to B10BR (H-2 k) mice induced low-levels of J8-specific IgG antibodies. While glycolipopeptides, in which J8 was covalently linked to the synthetic glycolipids, demonstrated high-levels of antibody titers comparable with the co-administration of these glycolipopeptides with complete Freund’s adjuvant, suggesting clearly the strong potency of the synthesized glycolipids as self-adjuvanting moieties.

New 3-O-Lauroyl-2-O-Benzyl-Glycerol Sulfonate

The hydroxy groups of D-mannitol were protected by the formation of acetals and benzylethers and then 2-O-benzyl-D-glyceraldehyde dimethylacetal was prepared after the deprotection and oxygenolysis of the protected D-mannitol. In the presence of DCC and DMAP, the lauroyl group was introduced at the primary hydroxyl group of the dimethylacetal and 3-O-lauroyl-2-O-benzyl-glycerol was obtained after the deprotection of the dimethylacetal with FeCl3·6H2O and then reduction with NaBH4. A series of new 3-O-lauroyl-2-O-benzyl-glycerol sulfonates was synthesised by the coupling of different sulfonyl groups with the 3-O-lauroyl-2-O-benzyl- glycerol. The bioactivities of the title compounds were tested and some compounds exhibited fungicidal activity against the tested fungi.

Secondary Acylation of Klebsiella pneumoniae Lipopolysaccharide Contributes to Sensitivity to Antibacterial Peptides

Klebsiella pneumoniae is an important cause of nosocomial Gram-negative sepsis. Lipopolysaccharide (LPS) is considered to be a major virulence determinant of this encapsulated bacterium and most mutations to the lipid A anchor of LPS are conditionally lethal to the bacterium. We studied the role of LPS acylation in K. pneumoniae disease pathogenesis by using a mutation of lpxM (msbB/waaN), which encodes the enzyme responsible for late secondary acylation of immature lipid A molecules. A K. pneumoniae B5055 (K2:O1) lpxM mutant was found to be attenuated for growth in the lungs in a mouse pneumonia model leading to reduced lethality of the bacterium. B5055DeltalpxM exhibited similar sensitivity to phagocytosis or complement-mediated lysis than B5055, unlike the non-encapsulated mutant B5055nm. In vitro, B5055DeltalpxM showed increased permeability of the outer membrane and an increased susceptibility to certain antibacterial peptides suggesting that in vivo attenuation may be due in part to sensitivity to antibacterial peptides present in the lungs of BALB/c mice. These data support the view that lipopolysaccharide acylation plays a important role in providing Gram-negative bacteria some resistance to structural and innate defenses and especially the antibacterial properties of detergents (e.g. bile) and cationic defensins.

Inhibition of interleukin-4 production in activated T cells via the downregulation of AP-1/NF-AT activation by N-lauroyl- d-erythro-sphingosine and N-lauroyl- d-erythro-C 20-sphingosine

Allergic diseases are hypersensitivity disorders that are associated with the generation of specific immunoglobulin E (IgE) in response to environmental allergens. Interleukin (IL)-4, which is primarily produced by the CD4 + T cells, is an important stimulus for the switching of the antibody isotype to IgE in both mice and humans. In a previous study, we demonstrated that ceramide derivatives coupled with a lauroyl group exerted strong inhibitory effects on IL-4 production in T cells. In this study, we attempted to characterize the mechanisms underlying the inhibition of IL-4 production in T cells. Two ceramide derivatives, N-lauroyl- d-erythro-sphingosine and N-lauroyl- d-erythro-C 20-sphingosine (hereafter abbreviated as LES and LECS, respectively), were shown to significantly inhibit the production of IL-4 in both primary CD4 + T cells and EL4 T thymoma cells in a dose-dependent manner. LES and LECS also inhibited the activity of the IL-4 gene promoter in EL4 cells transiently transfected with IL-4 gene promoter constructs, but this effect was impaired in EL4 cells that had been transfected with an IL-4 promoter construct deleted of a P4 site harboring the AP-1 and NF-AT binding sites. Furthermore, LES and LECS inhibited the DNA binding activities of both AP-1 and NF-AT transcription factors. In addition, LES and LECS were demonstrated to suppress PMA-stimulated PKC activity, although they exerted no significant effects on the protein levels of the conventional PKCs. These results indicate that the ceramides, LES and LECS, may inhibit the production of IL-4 in the activated T cells, via the downregulation of AP-1/NF-AT activation and PKC activity.