Fatty Acid Conjugates Research Articles

Mechanism of radioprotection by dihydroxy-1-selenolane (DHS): Effect of fatty acid conjugation and role of glutathione peroxidase (GPx)

Dihydroxy-1-selenolane (DHS) previously reported to exhibit radioprotective activity was investigated to understand its mechanism of action in CHO cells of epithelial origin. DHS pre-treatment at 25 μM for 16 h significantly protected CHO cells from radiation (4–11 Gy)-induced delayed mitotic cell death. Further to examine, how increased cellular uptake can influence this mechanism, studies have been performed with DHS-C6, a lipophilic conjugate of DHS. Accordingly CHO cells pre-treated with DHS-C6, showed increased survival against radiation exposure. Notably treatment with both DHS and DHS-C6 significantly increased glutathione peroxidase (GPx) activity in cells by ∼ 2.5 fold. Additionally, the compound DHS or DHS-C6 led to faster repair of DNA in irradiated cells and subsequently inhibited the G2/M arrest. Anticipating the role of GPx in radioprotection, our investigations revealed that addition of mercaptosuccinic acid, a pharmacological inhibitor of GPx reversed all the above effects of DHS or DHS-C6. Further inhibitors of check point kinase 1 (CHK1) and DNA-protein kinase (DNA-PK) although abrogated the radioprotective effect of DHS or DHS-C6 separately, did not show additive effect in combination with GPx inhibitor, suggesting their cross talk. In contrast to these results, both DHS and DHS-C6 treatment did not protect spleen lymphocytes from the radiation-induced apoptosis. Thus results confirmed that both DHS and DHS-C6 protected cells from radiation-induced mitotic death by augmenting DNA repair in a GPx dependant manner.

Biobased Oligomeric Esters Comprised of 1,3‐Propanediol, Succinic Acid, and Fatty Acids

AbstractOligomers derived from renewable compounds, 1,3‐propanediol and succinic acid, are prepared through a solution polymerization method to afford a series of alcohol‐terminated oligomers with different molecular weight distributions. Fatty acid conjugation to the alcohol‐terminated oligomers yields novel fatty acid‐capped oligomers with unique physical properties (ranging from amorphous oils and waxes to semi‐crystalline solids), which may be controlled by tuning the molecular weight and fatty acid end‐groups. To assess the potential of these new materials to replace petroleum‐based ingredients in personal care and cosmetic formulations (for use as, e.g., viscosity modifiers, surfactants, and film‐formers), the effect of molecular weight and end‐group chain length on solution viscosity and surface tensions is examined, finding that the relative viscosities of solutions containing these oligomers increase as a function of oligomer concentration and molecular weight, while the surface tensions decrease primarily as a function of the fatty acid end‐group chain length.

Role of the extracellular matrix-located Mac-2 binding protein as an interactor of the Wnt proteins

The Wnt proteins constitute a conserved family of secreted palmitoleate-containing signaling proteins that play important roles in development and tissue homeostasis. Their hydrophobic nature has raised the question of how the proteins are transported outside the cells. Accumulating evidence suggests that several different mechanisms, including transport by lipoprotein particles and exosomes, may contribute to this process. Here, we expressed epitope-tagged Wnt4 in HEK293 cells, and identified Mac-2 binding protein (Mac-2BP) as its binding partner in the serum-free conditioned medium. Serine-to-alanine substitution at the conserved fatty acid-conjugation site did not affect Mac-2BP binding. Subsequent studies showed that Mac-2BP may be a general Wnt interactor. It is found in the extracellular matrix (ECM) of various tissues, where it forms unusual oligomeric ring-like structures. Its functions appear to include interactions with cells and certain ECM components. Intriguingly, both Wnt signaling and Mac-2BP expression are upregulated in many types of cancer. Our studies on the four-domain Mac-2BP indicate a crucial role in Wnt binding for the C-terminal domain that bears no sequence similarity to any other protein. Mac-2BP may have a role in regulating the extracellular spreading and storage of the Wnts, thereby modulating their bioavailability and stability.

Tumor-targeted delivery of siRNA using fatty acyl-CGKRK peptide conjugates

Tumor-targeted carriers provide efficient delivery of chemotherapeutic agents to tumor tissue. CGKRK is one of the well-known tumor targeting peptides with significant specificity for angiogenic blood vessels and tumor cells. Here, we designed fatty acyl conjugated CGKRK peptides, based on the hypothesis that hydrophobically-modified CGKRK peptide could enhance cellular permeation and delivery of siRNA targeted to tumor cells for effective silencing of selected proteins. We synthesized six fatty acyl-peptide conjugates, using a diverse chain of saturated and unsaturated fatty acids to study the efficiency of this approach. At peptide:siRNA weight/weight ratio of 10:1 (N/P ≈ 13.6), almost all the peptides showed complete binding with siRNA, and at a w/w ratio of 20:1 (N/P ≈ 27.3), complete protection of siRNA from early enzymatic degradation was observed. Conjugated peptides and peptide/siRNA complexes did not show significant cytotoxicity in selected cell lines. The oleic acid-conjugated peptide showed the highest efficiency in siRNA uptake and silencing of kinesin spindle protein at peptide:siRNA w/w ratio of 80:1 (N/P ≈ 109). The siRNA internalization into non-tumorigenic kidney cells was negligible with all fatty acyl-peptide conjugates. These results indicate that conjugation of fatty acids to CGKRK could create an efficient delivery system for siRNA silencing specifically in tumor cells.

Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue

Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis.

Indirect plant defense against insect herbivores: a review.

Plants respond to herbivore attack by launching 2 types of defenses: direct defense and indirect defense. Direct defense includes all plant traits that increase the resistance of host plants to insect herbivores by affecting the physiology and/or behavior of the attackers. Indirect defense includes all traits that by themselves do not have significant direct impact on the attacking herbivores, but can attract natural enemies of the herbivores and thus reduce plant loss. When plants recognize herbivore-associated elicitors, they produce and release a blend of volatiles that can attract predators, parasites, and other natural enemies. Known herbivore-associated elicitors include fatty acid-amino acid conjugates, sulfur-containing fatty acids, fragments of cell walls, peptides, esters, and enzymes. Identified plant volatiles include terpenes, nitrogenous compounds, and indoles. In addition, constitive traits including extrafloral nectars, food bodies, and domatia can be further induced to higher levels and attract natural enemies as well as provide food and shelter to carnivores. A better understanding of indirect plant defense at global and componential levels via advanced high throughput technologies may lead to utilization of indirect defense in suppression of herbivore damage to plants.

Malvidin 3-Glucoside-Fatty Acid Conjugates: From Hydrophilic toward Novel Lipophilic Derivatives.

This work describes the lipophilization reactions of malvidin 3-glucoside with different saturated fatty acid chain lengths using an enzymatic synthesis and the study of their physical-chemical and antioxidant properties. The lipophilic anthocyanins were obtained with satisfactory yields (22-40%) after column chromatography purifications, and they revealed the same appealing chromatic features of the parent anthocyanin. All of the compounds were characterized by mass spectrometry, confirming the regioselective acylation on the glucose moiety. The octanol-water partition coefficients and the hydrophobicity index of the different derivatives were determined, confirming a lipophilicity increase concomitant with the fatty acid chain length. The antioxidant profile was also evaluated by using two in vitro methods (β-carotene-lineolate method and oxygen consumption assay). Overall, a maximum of antioxidant activity was achieved when malvidin 3-glucoside was conjugated with caprylic acid (C8). Altogether, the results obtained provide a good perspective for the technological application of these functionalized anthocyanins in the cosmetics and food industries.

A Strategy Combining Higher Energy C-Trap Dissociation with Neutral Loss- and Product Ion-Based MSn Acquisition for Global Profiling and Structure Annotation of Fatty Acids Conjugates.

Fatty acids conjugates (FACs) are ubiquitous but found in trace amounts in the natural world. They are composed of multiple unknown substructures and side chains. Thus, FACs are difficult to be analyzed by traditional mass spectrometric methods. In this study, an integrated strategy was developed to global profiling and targeted structure annotation of FACs in complex matrix by LTQ Orbitrap. Dicarboxylic acid conjugated bufotoxins (DACBs) in Venenum bufonis (VB) were used as model compounds. The new strategy (abbreviated as HPNA) combined higher-energy C-trap dissociation (HCD) with product ion- (PI), neutral loss- (NL) based MSn (n ≥ 3) acquisition in both positive-ion mode and negative-ion mode. Several advantages are presented. First, various side chains were found under HCD in negative-ion mode, which included both known and unknown side chains. Second, DACBs with multiple side chains were simultaneously detected in one run. Compared with traditional quadrupole-based mass method, it greatly increased analysis throughput. Third, the fragment ions of side chain and steroids substructure could be obtained by PI- and NL-based MSn acquisition, respectively, which greatly increased the accuracy of the structure annotation of DACBs. In all, 78 DACBs have been discovered, of which 68 were new compounds; 25 types of substructure formulas and seven dicarboxylic acid side chains were found, especially five new side chains, including two saturated dicarboxylic acids [(azelaic acid (C9) and sebacic acid (C10)] and three unsaturated dicarboxylic acids (u-C8, u-C9, and u-C10). All these results greatly enriched the structures of DACBs in VB. Graphical Abstract ᅟ.

N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2.

Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2 (PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

Design, Synthesis, and Evaluation of Dasatinib-Amino Acid and Dasatinib-Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors.

Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib-l-arginine derivative (Das-R, 7) was found to be the most potent of the inhibitors tested, with IC50 values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C10 ) with an IC50 value of 3.2 μm for Csk compared with 35 nm for Src. Furthermore, many compounds displayed increased selectivity toward Src over Abl. Compounds 15 (Das-glutamic acid) and 13 (Das-cysteine) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50 ratios). Das-R (IC50 =2.06 μm) was significantly more potent than the parent dasatinib (IC50 =26.3 μm) against Panc-1 cells, whereas both compounds showed IC50 <51.2 pm against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed good agreements with the experimental results and rationalized the differences in selectivity among the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of the dasatinib scaffold, providing useful insight into mechanisms of kinase selectivity.

Inducible De Novo Biosynthesis of Isoflavonoids in Soybean Leaves by Spodoptera litura Derived Elicitors: Tracer Techniques Aided by High Resolution LCMS.

Isoflavonoids are a characteristic family of natural products in legumes known to mediate a range of plant-biotic interactions. For example, in soybean (Glycine max: Fabaceae) multiple isoflavones are induced and accumulate in leaves following attack by Spodoptera litura (Lepidoptera: Noctuidae) larvae. To quantitatively examine patterns of activated de novo biosynthesis, soybean (Var. Enrei) leaves were treated with a combination of plant defense elicitors present in S. litura gut content extracts and L-α-[13C9, 15N]phenylalanine as a traceable isoflavonoid precursor. Combined treatments promoted significant increases in 13C-labeled isoflavone aglycones (daidzein, formononetin, and genistein), 13C-labeled isoflavone 7-O-glucosides (daidzin, ononin, and genistin), and 13C-labeled isoflavone 7-O-(6″-O-malonyl-β-glucosides) (malonyldaidzin, malonylononin, and malonylgenistin). In contrast levels of 13C-labeled flavones and flavonol (4',7-dihydroxyflavone, kaempferol, and apigenin) were not significantly altered. Curiously, application of fatty acid-amino acid conjugate (FAC) elicitors present in S. litura gut contents, namely N-linolenoyl-L-glutamine and N-linoleoyl-L-glutamine, both promoted the induced accumulation of isoflavone 7-O-glucosides and isoflavone 7-O-(6″-O-malonyl-β-glucosides), but not isoflavone aglycones in the leaves. These results demonstrate that at least two separate reactions are involved in elicitor-induced soybean leaf responses to the S. litura gut contents: one is the de novo biosynthesis of isoflavone conjugates induced by FACs, and the other is the hydrolysis of the isoflavone conjugates to yield isoflavone aglycones. Gut content extracts alone displayed no hydrolytic activity. The quantitative analysis of isoflavone de novo biosynthesis, with respect to both aglycones and conjugates, affords a useful bioassay system for the discovery of additional plant defense elicitor(s) in S. litura gut contents that specifically promote hydrolysis of isoflavone conjugates.

Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23–IL-17 signaling in macrophages

Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties.Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100–500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

Modulation of plant defense responses to herbivores by simultaneous recognition of different herbivore-associated elicitors in rice.

Induced plant defense responses against insect herbivores are triggered by wounding and/or perception of herbivore elicitors from their oral secretions (OS) and/or saliva. In this study, we analyzed OS isolated from two rice chewing herbivores, Mythimna loreyi and Parnara guttata. Both types of crude OS had substantial elicitor activity in rice cell system that allowed rapid detection of early and late defense responses, i.e. accumulation of reactive oxygen species (ROS) and defense secondary metabolites, respectively. While the OS from M. loreyi contained large amounts of previously reported insect elicitors, fatty acid-amino acid conjugates (FACs), the elicitor-active P. guttata’s OS contained no detectable FACs. Subsequently, elicitor activity associated with the high molecular mass fraction in OS of both herbivores was identified, and shown to promote ROS and metabolite accumulations in rice cells. Notably, the application of N-linolenoyl-Gln (FAC) alone had only negligible elicitor activity in rice cells; however, the activity of isolated elicitor fraction was substantially promoted by this FAC. Our results reveal that plants integrate various independent signals associated with their insect attackers to modulate their defense responses and reach maximal fitness in nature.

Development of Poly Unsaturated Fatty Acid Derivatives of Aspirin for Inhibition of Platelet Function.

The inhibition of platelet aggregation is key to preventing conditions such as myocardial infarction and ischemic stroke. Aspirin is the most widely used drug to inhibit platelet aggregation. Aspirin absorption can be improved further to increase its permeability across biologic membranes via esterification or converting the carboxylic acid to an anhydride. There are several reports indicating that ω-3 and ω-6 fatty acids such as linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) separately inhibit platelet aggregation. Herein, we synthesize anhydride conjugates of aspirin with linoleic acid, EPA, and DHA to form aspirin anhydrides that are expected to have higher permeability across cellular membranes. These aspirin-fatty acid anhydrides inhibited platelet aggregation in washed human platelets and platelet-rich plasma in a dose-dependent manner. In particular, the aspirin-DHA anhydride displayed similar effectiveness to aspirin. Platelet aggregation studies conducted in the presence of various platelet agonists indicated that the aspirin-lipid conjugates act through inhibition of the cyclooxygenase (COX)-thromboxane synthase (TXAS) pathway. Hence, we performed detailed biochemical studies using purified COX-1 as well as TXAS stabilized in nanoscale lipid bilayers of nanodiscs to confirm results from the platelet aggregation studies. We show that although all of the aspirin conjugates act through the COX-TXAS pathway by inhibiting COX-1, the parent fatty acids do not act via this pathway. Finally, we studied the hydrolysis of these compounds in buffer and human plasma, and we demonstrate that all of the aspirin-fatty acid conjugates hydrolyze to the parent molecules aspirin and fatty acid in a controlled manner.

Auxin Is Rapidly Induced by Herbivore Attack and Regulates a Subset of Systemic, Jasmonate-Dependent Defenses.

Plant responses to herbivore attack are regulated by phytohormonal networks. To date, the role of the auxin indole-3-acetic acid (IAA) in this context is not well understood. We quantified and manipulated the spatiotemporal patterns of IAA accumulation in herbivore-attacked Nicotiana attenuata plants to unravel its role in the regulation of plant secondary metabolism. We found that IAA is strongly, rapidly, and specifically induced by herbivore attack. IAA is elicited by herbivore oral secretions and fatty acid conjugate elicitors and is accompanied by a rapid transcriptional increase of auxin biosynthetic YUCCA-like genes. IAA accumulation starts 30 to 60 s after local induction and peaks within 5 min after induction, thereby preceding the jasmonate (JA) burst. IAA accumulation does not require JA signaling and spreads rapidly from the wound site to systemic tissues. Complementation and transport inhibition experiments reveal that IAA is required for the herbivore-specific, JA-dependent accumulation of anthocyanins and phenolamides in the stems. In contrast, IAA does not affect the accumulation of nicotine or 7-hydroxygeranyllinalool diterpene glycosides in the same tissue. Taken together, our results uncover IAA as a rapid and specific signal that regulates a subset of systemic, JA-dependent secondary metabolites in herbivore-attacked plants.

Physiological function and ecological aspects of fatty acid-amino acid conjugates in insects.

In tritrophic interactions, plants recognize herbivore-produced elicitors and release a blend of volatile compounds (VOCs), which work as chemical cues for parasitoids or predators to locate their hosts. From detection of elicitors to VOC emissions, plants utilize sophisticated systems that resemble the plant-microbe interaction system. Fatty acid-amino acid conjugates (FACs), a class of insect elicitors, resemble compounds synthesized by microbes in nature. Recent evidence suggests that the recognition of insect elicitors by an ancestral microbe-associated defense system may be the origin of tritrophic interactions mediated by FACs. Here we discuss our findings in light of how plants have customized this defense to be effective against insect herbivores, and how some insects have successfully adapted to these defenses.

Synthesis, characterization and evaluation of antiproliferative activity of diisopropylphenyl esters of fatty acids from selected oils

The present investigation describes the synthesis, characterization and evaluation of antiproliferative activity of novel diisopropylphenol (propofol) conjugates of fatty acids. The fatty acids were obtained from oils of Jatropha curcas (jatropha) and Pongamia glabra (karanja) containing unsaturated-rich fatty acids, Sterculia foetida (containing cyclopropene-rich fatty acids), Samia cynthia (eri pupae, containing polyunsaturated-rich fatty acid, 18:3) and Cocos nucifera (coconut, containing medium-chain saturated-rich fatty acids). The synthesized conjugates viz. propofol-jatropha mixed fatty acid conjugates (2,4P-JTA and 2,6P-JTA), propofol-karanja mixed fatty acid conjugates (2,4P-KTA and 2,6P-KTA), propofol-sterculia foetida mixed fatty acid conjugates (2,4P-STA and 2,6P-STA), propofol-eri pupal mixed fatty acid conjugates (2,4P-EFA and 2,6-EFA) and propofol-coconut mixed fatty acid conjugates (2,4P-CCFA and 2,6P-CCFA) were obtained by esterification of the fatty acid mixture to propofol isomers (2,4-diisopropylphenol and 2,6-diisopropylphenol). The prepared derivatives were characterized by FT-IR, NMR (1H, 13C) and GC–MS and were tested for in vitro antiproliferative studies on A549, MDA-MB-231, HeLa, Mia-Pa–Ca and HePG2 cancer cell lines. All the synthesized propofol-mixed fatty acid conjugates showed good to moderate specific growth inhibition of cancer cells on studied cell lines. The results suggest that all the novel propofol-mixed fatty acid conjugates possess antiproliferative properties that reduce the proliferation of cancer cells in vitro.

Platinum (IV)-fatty acid conjugates overcome inherently and acquired Cisplatin resistant cancer cell lines: an in-vitro study.

BackgroundPlatinum-based drugs are used as cancer chemotherapeutics for the last 40 years. However, drug resistance and nephrotoxicity are the major limitations of the use of platinum-based compounds in cancer therapy. Platinum (IV) complexes are believed to act as platinum prodrugs and are able to overcome some of platinum (II) limitations.MethodsA number of previously sensitized platinum (IV) complexes were evaluated for their anti-cancer activity by monitoring ability to affect proliferation, clonigenicity and apoptosis induction of Cisplatin sensitive and resistant cancer cells. In addition, the uptake of Cisplatin and the platinum (IV) derivatives to Cisplatin sensitive and resistant cancer cells was monitored.ResultsThe bis-octanoatoplatinum (IV) complex (RJY13), a Cisplatin derivative with octanoate as axial ligand, exhibited strong anti-proliferative effect on the Cisplatin resistant and sensitive ovarian cells, A2780cisR and A2780, respectively. Moreover, RJY13 exhibited good activity in inhibiting clonigenicity of both cells. Anti-proliferative activity of RJY13 was mediated by induction of apoptosis. Interestingly, a bis-lauratopaltinum (IV) complex (RJY6) was highly potent in inhibiting clonigenicity of both Cisplatin sensitive and Cisplatin resistant cells, however, exhibited reduced activity in assays that utilize cells growing in two dimensional (2D) conditions. The uptake of Cisplatin was reduced by 30 % in A2780 in which the copper transporter-1 (Ctr1) was silenced. Moreover, uptake of RJY6 was marginally dependent on Ctr1, while uptake of RJY13 was Ctr1-independent.ConclusionsOur data demonstrated the potential of platinum (IV) prodrugs in overcoming acquired and inherited drug resistance in cancer cell lines. Moreover, our data demonstrated that the uptake of Cisplatin is partially dependent on Ctr1 transporter, while uptake of RJY6 is marginally dependent on Ctr1 and RJY13 is Ctr1-independent. In addition, our data illustrated the therapeutic potential of platinum (IV) prodrugs in cancer therapy.

Synthesis and Characterization of Fatty Acid Conjugates of Niacin and Salicylic Acid.

This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.

Crystal structure of the N-myristoylated lipopeptide-bound MHC class I complex.

The covalent conjugation of a 14-carbon saturated fatty acid (myristic acid) to the amino-terminal glycine residue is critical for some viral proteins to function. This protein lipidation modification, termed N-myristoylation, is targeted by host cytotoxic T lymphocytes (CTLs) that specifically recognize N-myristoylated short peptides; however, the molecular mechanisms underlying lipopeptide antigen (Ag) presentation remain elusive. Here we show that a primate major histocompatibility complex (MHC) class I-encoded protein is capable of binding N-myristoylated 5-mer peptides and presenting them to specific CTLs. A high-resolution X-ray crystallographic analysis of the MHC class I:lipopeptide complex reveals an Ag-binding groove that is elaborately constructed to bind N-myristoylated short peptides rather than prototypic 9-mer peptides. The identification of lipopeptide-specific, MHC class I-restricted CTLs indicates that the widely accepted concept of MHC class I-mediated presentation of long peptides to CTLs may need some modifications to incorporate a novel MHC class I function of lipopeptide Ag presentation.