168982-69-2

Usage

Uses

Used in Immunomodulation:
3-Oxo-N-[(3S)-tetrahydro-2-oxo-3-furanyl]dodecanamide is used as an immunomodulatory agent for its ability to inhibit lymphocyte proliferation and TNF-α and IL-12 production by LPS-stimulated macrophages. This property makes it a potential candidate for the development of therapeutic agents targeting inflammatory and immune-related disorders.
Used in Vaccine Adjuvants:
In the field of vaccine development, 3-Oxo-N-[(3S)-tetrahydro-2-oxo-3-furanyl]dodecanamide is used as an adjuvant to modulate the immune response. It has been shown to inhibit or promote antibody production at high and low concentrations, respectively, in keyhole limpet hemocyanin (KLH)-stimulated spleen cells. This dual action could be harnessed to enhance the effectiveness of vaccines by fine-tuning the immune response.
Used in Pharmaceutical Industry:
3-Oxo-N-[(3S)-tetrahydro-2-oxo-3-furanyl]dodecanamide is used as a research tool in the pharmaceutical industry for studying the mechanisms of bacterial quorum sensing and its impact on host-pathogen interactions. Understanding these mechanisms can lead to the development of novel therapeutic strategies targeting bacterial infections and their associated complications.

Biochem/physiol Actions

N-(3-oxododecanoyl)homoserine-L-lactone (3-oxo-C12-HSL) is among a group of homoserine lactones that includes: N-octanoyl-homoserine lactone (N-C8-HSL), N-(3-oxodecanoyl) homoserine-L-lactone (3-oxo-C10 HSL), N-(3-Oxotetradecanoyl)-L-homoserine lactone (3-oxo-C14-HSL, N-(3-hydroxydecanoyl)-L-homoserine lactone, and N-(3-hydroxyoctanoyl)-L-homoserine lactone involved in the processes of bacterial quorum sensing. These N-acyl-homoserine lactones are used to study the processes and mechanisms of bacterial quorum sensing.

references

[1]. henke jm, bassler bl. bacterial social engagements. trends cell biol. 2004 nov;14(11):648-56.[2]. chambers ce, visser mb, schwab u, et al. identification of n-acylhomoserine lactones in mucopurulent respiratory secretions from cystic fibrosis patients. fems microbiol lett. 2005 mar 15;244(2):297-304.[3]. smith rs, fedyk er, springer ta, et al. il-8 production in human lung fibroblasts and epithelial cells activated by the pseudomonas autoinducer n-3-oxododecanoyl homoserine lactone is transcriptionally regulated by nf-kappa b and activator protein-2. j immunol. 2001 jul 1;167(1):366-74.

Upstream product

• 61058-75-1 3-oxo-dodecanoic acid 
• 2185-02-6 L-homoserine lactone 
• 2185-03-7 L-homoserine lactone hydrochloride 
• 429675-23-0 5-(1-hydroxydecylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 596104-60-8 (2-nonyl-[1,3]dioxolan-2-yl)-acetic acid 
• 71989-28-1 N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-methionine 
• 76835-64-8 methyl 3-oxododecanoate 
• 112-13-0 n-decanoyl chloride 
• 6305-38-0 (S)-(-)-α-amino-γ-butyrolactone hydrobromide 
• 182359-65-5 5-decanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 182359-61-1 (S)-2-(2-nonyl-1,3-dioxolan-2-yl)-N-(2-oxotetrahydrofuran-3-yl)acetamide 
• 19444-84-9 3-deoxy-L-glycero-tetronolactone 
• 112-12-9 methyl nonyl ketone 
• 334-48-5 1-decanoic acid 

Downstream Products

• 182359-60-0 N-(3-hydroxy-dodecanoyl)-L-homoserine lactone 

Relevant academic research and scientific papers

Synthesis of new chalcone-based homoserine lactones and their antiproliferative activity evaluation

Three series of new homoserine lactone analogs were efficiently synthesized starting from methionine and further evaluated for their antiproliferative activity against different cancer cell lines. Among these compounds, some of the chalcone containing compounds 6a-n showed acceptable antiproliferative activity against prostate cancer cells DU145 and PC-3 with the IC50 values less than 10 μM. Compounds 6c, 6e and 6h inhibited growth of DU145 and PC-3 cells at low micromolar levels with the IC50 values ranging from 3.0 to 5.0 μM, much more potent than natural OdDHL. Compound 6e concentration-dependently inhibited colony formation and cell migration of DU145 cells. A synergistic effect on the growth inhibition and the apoptosis of DU145 cells was observed when compound 6e was used in combination with TRAIL. OdDHL or 6e treatment concentration-dependently activated TRAIL death receptor DR5 which may account for the observed synergistic effect of 6e or OdDHL with TRAIL on the growth inhibition and cell apoptosis. Compound 6e also inhibited migration of DU145 cells in a time- and concentration-dependent manner. The data suggest that quorum sensing molecules OdDHL and 6e may improve the sensitivity of DU145 cells toward TRAIL via activating DR5, compound 6e may be used as a potential lead compound for developing new TRAIL receptor agonists.

Identification and Quantification of N-Acyl Homoserine Lactones Involved in Bacterial Communication by Small-Scale Synthesis of Internal Standards and Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

N-acyl homoserine lactones (AHL) are small signal molecules involved in the quorum sensing of many gram-negative bacteria, and play an important role in biofilm formation and pathogenesis. Present analytical methods for identification and quantification of AHL require time-consuming sample preparation steps and are hampered by the lack of appropriate standards. By aiming at a fast and straightforward method for AHL analytics, we investigated the applicability of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Suitable MALDI matrices, including crystalline and ionic liquid matrices, were tested and the fragmentation of different AHL in collision-induced dissociation MS/MS was studied, providing information about characteristic marker fragments ions. Employing small-scale synthesis protocols, we established a versatile and cost-efficient procedure for fast generation of isotope-labeled AHL standards, which can be used without extensive purification and yielded accurate standard curves. Quantitative analysis was possible in the low pico-molar range, with lower limits of quantification reaching from 1 to 5 pmol for different AHL. The developed methodology was successfully applied in a quantitative MALDI MS analysis of low-volume culture supernatants of Pseudomonas aeruginosa. [Figure not available: see fulltext.].

Molecular insights into the impact of oxidative stress on the quorum-sensing regulator protein LasR

The LasR regulator protein functions at the top of the Pseudomonas aeruginosa quorum-sensing hierarchy and is implicated in promoting bacterial virulence. Of note is recent evidence that this transcription factor may also respond to oxidative stress. Here, all cysteines in LasR were inspected to deduce their redox sensitivity and to probe the connection between stress response and LasR activity using purified LasR and individual LasR domains. Cys79 in the ligand binding domain of LasR appears to be important for ligand recognition and folding of this domain to potentiate DNA binding but does not seem to be sensitive to oxidative stress when bound to its native ligand. Two cysteines in the DNA binding domain of LasR do form a disulfide bond when treated with hydrogen peroxide, and formation of this Cys201-Cys203 disulfide bond appears to disrupt the DNA binding activity of the transcription factor. Mutagenesis of either of these cysteines leads to expression of a protein that no longer binds DNA. A cell-based reporter assay linking LasR function with β-galactosidase activity gave results consistent with those obtained with purified LasR. This work provides a possible mechanism for oxidative stress response by LasR and indicates that multiple cysteines within the protein may prove to be useful targets for disabling its activity.

Discovery of novel AHLs as potent antiproliferative agents

Three series of novel AHL analogs were synthesized and evaluated for their in vitro cytotoxic activity against four human cancer cell lines. The SARs investigation indicated that AHLs with a terminal phenyl group, especially those with the chalcone scaffold had remarkably enhanced cytotoxicity than those with the hydrophobic side chains. Besides, some of these compounds were much more potent than 5-Fu and natural OdDHL. Through the detailed SARs discussions, we found that compounds 10a-k and 14 with the 4-amino chalcone scaffold showed excellent inhibition against all the tested cancer cell lines and were much more potent than 5-Fu and AHLs. Such scaffold may act as a template for further lead optimization. Compound 10i with a 3, 4, 5-trimethoxy group was the most potent one against all the tested cancer cell lines. Flow cytometry analysis indicated that analog 11e induced the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner.

Haloperoxidase mediated quorum quenching by Nitzschia cf pellucida: Study of the metabolization of N-Acyl homoserine lactones by a benthic diatom

Diatoms are known to produce a variety of halogenated compounds, which were recently shown to have a role in allelopathic interactions between competing species. The production of these compounds is linked to haloperoxidase activity. This research, has shown that this system may also be involved in diatom-bacteria interactions via the H2O2 dependent inactivation of a type of quorum sensing (QS) molecule, i.e., N-β-ketoacylated homoserine lactones (AHLs), by a natural haloperoxidase system from the benthic diatom Nitzschia cf pellucida. The AHL degradation pathway towards corresponding halogenated derivatives was elucidated via HPLC-MS analysis and the synthesis of a broad series of novel halogenated AHL analogues as reference compounds. Furthermore, their biological activity as quorum sensing modulators was directly compared and evaluated against a series of naturally occurring β-keto-AHLs. It has been demonstrated that the loss of the QS activity results from the final cleavage of the halogenated N-acyl chain of the signal molecules.

Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors

A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

Deuterium and tritium labelling of N-acyl-L-homoserine lactones (AHLs) by catalytic reduction of a double bond in the layer-by-layer method

N-Acyl-L-homoserine lactones (AHLs) are signalling molecules found in Gram-negative bacteria that enable bacteria to communicate with each other through quorum sensing and with their eukaryotic host cells through inter-kingdom signalling. Very little is known about inter-kingdom signalling mechanisms. Deuterium- and tritium-labelled AHLs were synthesized in an effort to detect the cellular distribution and monitor the membrane transport of AHLs. Most tritium labelling methods use tritium gas, which is difficult to handle, however, here we present a novel, gas-free method with which to obtain deuterium- and tritium-label terminally unsaturated AHLs through catalytic reduction of the double bond. This uncommon double bond reduction employs either sodium borohydride-[2H] or sodium borohydride-[3H] and is performed in the presence of palladium(II) acetate, which acts as a catalyst in the unique layer-by-layer system. Moreover, detailed NMR analysis of the resulting isotopologues is presented. A novel, gas-free method of deuterium- and tritium-labelling of terminally unsaturated AHLs is described. The catalytic reduction of the double bond by sodium borohydrides is performed in the presence of palladium(II) acetate, which acts as a catalyst in the unique layer-by-layer system. Copyright

Robust routes for the synthesis of N-acylated-l-homoserine lactone (AHL) quorum sensing molecules with high levels of enantiomeric purity

The ready availability of native quorum sensing molecules and related structural analogues is of significant biological interest in the development of methods to manipulate bacterial quorum sensing systems in a useful fashion. In this Letter we report robust routes for the synthesis of a range of N-acylated-l-homoserine lactone (AHL) quorum sensing molecules. Crucially, we have analysed the enantiopurity of the final AHLs and in all cases, excellent levels were observed.

Absolute configuration and antimicrobial activity of acylhomoserine lactones

(S)-N-Heptanoylhomoserine lactone is an uncommon acyl odd-chain natural product employed by many Gram-negative bacteria as a signaling substance in chemical communication mechanisms known as quorum sensing. The absolute configuration determination of the metabolite produced by the phytopathogen Pantoea ananatis Serrano is reported herein. As with all other substances of this class, the lactone moiety possesses S configuration, corroborating the hypothesis that it shares the same biosynthetic pathway as the (S)-N-hexanoylhomoserine lactone and also that some LuxI homologues can accept both hexanoyl- and heptanoyl-ACP as precursors. Evaluation of the antimicrobial activity of enantiomeric acylhomoserine lactones against three Gram-positive bacteria (Bacillus cereus, B. subtilis, and Staphylococcus aureus) revealed important features between absolute configuration and antimicrobial activity. The N-heptanoylhomoserine lactone was considerably less active than the 3-oxo derivatives. Surprisingly, non-natural (R)-N-(3-oxo-octanoyl)homoserine lactone was as active as the S enantiomer against B. cereus, while the synthetic racemic product was less active than either enantiomer.

MODULATION OF BACTERIAL QUORUM SENSING WITH SYNTHETIC LIGANDS

The present invention provides compounds and methods for modulation of the quorum sensing of bacteria. In an embodiment, the compounds of the present invention are able to act as replacements for naturally occurring bacterial quorum sensing ligands in a l