Ether Glycerophospholipids Research Articles

Decoding the Expressions, Immune Relevance, and Prognostic Values of Ferroptosis Gene TMEM189: A Pan-Cancer Analysis.

TMEM189 is a recently discovered transmembrane protein involved in ether glycerophospholipid synthesis and ferroptosis regulation. However, its role in tumors are not well understood. To elucidate the oncogenic effects and prognostic values of TMEM189 in tumors. We performed a pan-cancer analysis of TMEM189 using various databases, bioinformatics and statistical tools, and tissue microarray analysis. TMEM189 is generally upregulated in tumors compared to normal tissues. High TMEM189 expression is linked to reduced promoter methylation. TMEM189 exhibits a negative correlation with immunogenic markers, immune cell infiltration, and expression of immune checkpoint genes (ICGs) in most cancers, implicating its immunosuppressive role in tumor microenvironments (TME). The interacting and similar genes with TMEM189 were involved in hotspot signaling pathways in pan-cancer. TMEM189 overexpression is usually associated with poor prognosis, especially an independent prognostic risk factor for BLCA, BRCA, LUAD, MESO, LIHC and SKCM. TMEM189 is overexpressed and exerts immunosuppressive effects in many tumors with a significant association with poor prognosis, suggesting its potential as a therapeutic target in cancer treatment.

Biochemical and Signaling Functions of Plasmalogens in the Norm and in Various Diseases

Plasmalogens (PL) are alkenyl ether glycerophospholipids that perform many physiologically important functions in the body and have a variety of properties. The role of PLs as endogenous antioxidants is well studied, as well as PLs that determine the physicochemical properties of biomembranes, deposit polyunsaturated fatty acids, participate in cholesterol biosynthesis, the process of ferroptosis and adaptation of cells to hypoxia, are sources for the synthesis of platelet activating factor and act as its antagonists. At the same time, LPs are involved in the pathogenesis of neurodegenerative, inflammatory, oncological diseases and a number of other pathologies. These conditions are united by the development of chronic inflammation and oxidative stress, accompanied by a change in the activity of synthesis and the content of PL in cells. Despite the fact that PL replacement therapy inhibits inflammation, the molecular mechanisms of the association of PL with inflammation have not been fully elucidated. The purpose of this review is to summarize the latest literature data on the structure, biosynthesis, and functions of PL, their relationship with signaling cascades involved in the pathogenesis of chronic inflammatory and neuroinflammatory diseases, as well as to show current achievements and future prospects for the use of PL in the treatment of certain diseases.

Transient Ca2+ entry by plasmalogen-mediated activation of receptor potential cation channel promotes AMPK activity.

Ethanolamine-containing alkenyl ether glycerophospholipids, plasmalogens, are major cell membrane components of mammalian cells that activate membrane protein receptors such as ion transporters and G-protein coupled receptors. However, the mechanism by which plasmalogens modulate receptor function is unknown. Here, we found that exogenously added plasmalogens activate transient receptor potential cation channel subfamily C member 4 (TRPC4) to increase Ca2+ influx, followed by calcium/calmodulin-dependent protein kinase 2-mediated phosphorylation of AMP-activated protein kinase (AMPK). Upon topical application of plasmalogens to the skin of mice, AMPK activation was observed in TRPC4-expressing hair bulbs and hair follicles. Here, TRPC4 was co-localized with the leucine-rich repeat containing G protein-coupled receptor 5, a marker of hair-follicle stem cells, leading to hair growth. Collectively, this study indicates that plasmalogens could function as gate openers for TRPC4, followed by activating AMPK, which likely accelerates hair growth in mice.

Structural Characterization and Quantitation of Ether-Linked Glycerophospholipids in Peroxisome Biogenesis Disorder Tissue by Ultraviolet Photodissociation Mass Spectrometry.

The biological impact of ether glycerophospholipids (GP) in peroxisomal disorders and other diseases makes them significant targets as biomarkers for diagnostic assays or deciphering pathology of the disorders. Ether lipids include both plasmanyl and plasmenyl lipids, which each contain an ether or a vinyl ether bond at the sn-1 linkage position, respectively. This linkage, in contrast to traditional diacyl GPs, precludes their detailed characterization by mass spectrometry via traditional collisional-based MS/MS techniques. Additionally, the isomeric nature of plasmanyl and plasmenyl pairs of ether lipids introduces a further level of complexity that impedes analysis of these species. Here, we utilize 213 nm ultraviolet photodissociation mass spectrometry (UVPD-MS) for detailed characterization of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) plasmenyl and plasmanyl lipids in mouse brain tissue. 213 nm UVPD-MS enables the successful differentiation of these four ether lipid subtypes for the first time. We couple this UVPD-MS methodology to reversed-phase liquid chromatography (RPLC) for characterization and relative quantitation of ether lipids from normal and diseased (Pex7 deficiency modeling the peroxisome biogenesis disorder, RCDP) mouse brain tissue, highlighting the ability to pinpoint specific structural features of ether lipids that are important for monitoring aberrant lipid metabolism in peroxisomal disorders.

Serine ether glycerophospholipids: Decrements in the frontal cortex associated with mild cognitive impairment and Alzheimer's disease.

Ether glycerophospholipids (GPL) are involved in membrane fluidity and fusion. Vinyl-ether GPL are also conjectured to provide antioxidant capacity in the brain. The roles of these lipids in the processes involved in the development of dementia are not understood but choline and ethanolamine vinyl-ether GPL (i.e., plasmalogens) are decreased in the brains of subjects with dementia. In contrast, serine ether and vinyl-ether GPL have not been investigated in human brain. We therefore undertook an evaluation of these lipids, utilizing high-resolution mass spectrometry (HR-MS), in tissues from control and dementia subjects that we had previously characterized in-depth. We can report for the first time that a number of serine ether GPL and a more limited number of serine plasmalogens are present in human frontal cortex. In addition, we found that some of these frontal cortex lipids are decreased in Mild Cognitive Impairment (MCI), early-onset Alzheimer’s disease (EOAD), and late-onset AD (LOAD). In contrast no alterations in serine ether GPL were monitored in the frontal cortex of donors with schizophrenia, demonstrating disease specificity. These data suggest that further studies of the roles of ether GPL, including serine ether GPL, in brain function are worthy of undertaking.

Coronavirus-Induced Host Cubic Membranes and Lipid-Related Antiviral Therapies: A Focus on Bioactive Plasmalogens.

Coronaviruses have lipid envelopes required for their activity. The fact that coronavirus infection provokes the formation of cubic membranes (CM) (denoted also as convoluted membranes) in host cells has not been rationalized in the development of antiviral therapies yet. In this context, the role of bioactive plasmalogens (vinyl ether glycerophospholipids) is not completely understood. These lipid species display a propensity for non-lamellar phase formation, facilitating membrane fusion, and modulate the activity of membrane-bound proteins such as enzymes and receptors. At the organism level, plasmalogen deficiency is associated with cardiometabolic disorders including obesity and type 2 diabetes in humans. A straight link is perceived with the susceptibility of such patients to SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) infection, the severity of illness, and the related difficulty in treatment. Based on correlations between the coronavirus-induced modifications of lipid metabolism in host cells, plasmalogen deficiency in the lung surfactant of COVID-19 patients, and the alterations of lipid membrane structural organization and composition including the induction of CM, we emphasize the key role of plasmalogens in the coronavirus (SARS-CoV-2, SARS-CoV, or MERS-CoV) entry and replication in host cells. Considering that plasmalogen-enriched lung surfactant formulations may improve the respiratory process in severe infected individuals, plasmalogens can be suggested as an anti-viral prophylactic, a lipid biomarker in SARS-CoV and SARS-CoV-2 infections, and a potential anti-viral therapeutic component of lung surfactant development for COVID-19 patients.

Distinct Functions of Acyl/Alkyl Dihydroxyacetonephosphate Reductase in Peroxisomes and Endoplasmic Reticulum.

Plasmalogens are a subclass of ether glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position of the glycerol backbone. Plasmalogen biosynthesis is initiated in peroxisomes. At the third step of plasmalogen synthesis, alkyl-dihydroxyacetonephosphate (DHAP) is enzymatically reduced to 1-alkyl-sn-glycero-3-phospate by acyl/alkyl DHAP reductase (ADHAPR), whose activity is found in both peroxisomes and microsomes. We herein show that knockdown of ADHAPR in HeLa cells reduced the synthesis of ethanolamine plasmalogen (PlsEtn), similar to the Chinese hamster ovary cell mutant FAA.K1B deficient in ADHAPR activity. Endogenous ADHAPR and ectopically expressed FLAG-tagged ADHAPR were localized to peroxisomes and endoplasmic reticulum (ER) as a type I integral membrane protein in HeLa cells. ADHAPR targets to peroxisomes via a Pex19p-dependent class I pathway. In addition, it is also inserted into the ER via the SRP-dependent mechanism. The ADHAPR mutant lacking the N-terminal domain preferentially targets to the ER, restoring the reduced level of PlsEtn synthesis in FAA.K1B cell. In contrast, the expression of full-length ADHAPR in the mutant cells elevates the synthesis of phosphatidylethanolamine, but not PlsEtn. Taken together, these results suggest that the third step of plasmalogen synthesis is mediated by ER-localized ADHAPR.

Structural Elucidation of Ether Glycerophospholipids Using Gas-Phase Ion/Ion Charge Inversion Chemistry.

Ether lipids represent a unique subclass of glycerophospholipid (GPL) that possesses a 1-O-alkyl (i.e., plasmanyl subclass) or a 1-O-alk-1'-enyl (i.e., plasmenyl subclass) group linked at the sn-1 position of the glycerol backbone. As changes in ether GPL composition and abundance are associated with numerous human pathologies, analytical strategies capable of providing high-level structural detail are desirable. While mass spectrometry (MS) has emerged as a prominent tool for lipid structural elucidation in biological extracts, distinctions between the various isomeric forms of ether-linked GPLs have remained a significant challenge for tandem MS, principally due to similarities in the conventional tandem mass spectra obtained from the two ether-linked subclasses. To distinguish plasmanyl and plasmenyl GPLs, a multistage (i.e., MSn where n = 3 or 4) mass spectrometric approach reliant on low-energy collision-induced dissociation (CID) is required. While this method facilitates assignment of the sn-1 bond type (i.e., 1-O-alkyl versus 1-O-alk-1'-enyl), a composite distribution of isomers is left unresolved, as carbon-carbon double-bond (C=C) positions cannot be localized in the sn-2 fatty acyl substituent. In this study, we combine a systematic MSn approach with two unique gas-phase charge inversion ion/ion chemistries to elucidate ether GPL structures with high-level detail. Ultimately, we assign both the sn-1 bond type and sites of unsaturation in the sn-2 fatty acyl substituent using an entirely gas-phase MS-based workflow. Application of this workflow to human blood plasma extract permitted isomeric resolution and in-depth structural identification of major and, in some cases, minor isomeric contributors to ether GPLs that have been previously unresolved when examined via conventional methods.

The glycosomal alkyl-dihydroxyacetonephosphate synthase TbADS is essential for the synthesis of ether glycerophospholipids in procyclic trypanosomes

Glycerophospholipids are the main constituents of the biological membranes in Trypanosoma brucei, which causes sleeping sickness in humans. The present work reports the characterization of the alkyl-dihydroxyacetonephosphate synthase TbADS that catalyzes the committed step in ether glycerophospholipid biosynthesis. TbADS localizes to the glycosomal lumen. TbADS complemented a null mutant of Leishmania major lacking alkyl-dihydroxyacetonephosphate synthase activity and restored the formation of normal form of the ether lipid based virulence factor lipophosphoglycan. Despite lacking alkyl-dihydroxyacetonephosphate synthase activity, a null mutant of TbADS in procyclic trypanosomes remained viable and exhibited normal growth. Comprehensive analysis of cellular glycerophospholipids showed that TbADS was involved in the biosynthesis of all ether glycerophospholipid species, primarily found in the PE and PC classes.

Peroxisomes protect lymphoma cells from HDAC inhibitor-mediated apoptosis

Peroxisomes are a critical rheostat of reactive oxygen species (ROS), yet their role in drug sensitivity and resistance remains unexplored. Gene expression analysis of clinical lymphoma samples suggests that peroxisomes are involved in mediating drug resistance to the histone deacetylase inhibitor (HDACi) Vorinostat (Vor), which promotes ROS-mediated apoptosis. Vor augments peroxisome numbers in cultured lymphoma cells, concomitant with increased levels of peroxisomal proteins PEX3, PEX11B, and PMP70. Genetic inhibition of peroxisomes, using PEX3 knockdown, reveals that peroxisomes protect lymphoma cells against Vor-mediated cell death. Conversely, Vor-resistant cells were tolerant to elevated ROS levels and possess upregulated levels of (1) catalase, a peroxisomal antioxidant, and (2) plasmalogens, ether glycerophospholipids that represent peroxisome function and serve as antioxidants. Catalase knockdown induces apoptosis in Vor-resistant cells and potentiates ROS-mediated apoptosis in Vor-sensitive cells. These findings highlight the role of peroxisomes in resistance to therapeutic intervention in cancer, and provide a novel modality to circumvent drug resistance.

The Trypanosoma brucei dihydroxyacetonephosphate acyltransferase TbDAT is dispensable for normal growth but important for synthesis of ether glycerophospholipids.

Glycerophospholipids are the most abundant constituents of biological membranes in Trypanosoma brucei, which causes sleeping sickness in humans and nagana in cattle. They are essential cellular components that fulfill various important functions beyond their structural role in biological membranes such as in signal transduction, regulation of membrane trafficking or control of cell cycle progression. Our previous studies have established that the glycerol-3-phosphate acyltransferase TbGAT is dispensable for growth, viability, and ester lipid biosynthesis suggesting the existence of another initial acyltransferase(s). This work presents the characterization of the alternative, dihydroxyacetonephosphate acyltransferase TbDAT, which acylates primarily dihydroxyacetonephosphate and prefers palmitoyl-CoA as an acyl-CoA donor. TbDAT restores the viability of a yeast double null mutant that lacks glycerol-3-phosphate and dihydroxyacetonephosphate acyltransferase activities. A conditional null mutant of TbDAT in T. brucei procyclic form was created and characterized. TbDAT was important for survival during stationary phase and synthesis of ether lipids. In contrast, TbDAT was dispensable for normal growth. Our results show that in T. brucei procyclic forms i) TbDAT but not TbGAT is the physiologically relevant initial acyltransferase and ii) ether lipid precursors are primarily made by TbDAT.

Plasmalogen enrichment in exosomes secreted by a nematode parasite versus those derived from its mouse host: implications for exosome stability and biology

Extracellular vesicles (EVs) mediate communication between cells and organisms across all 3 kingdoms of life. Several reports have demonstrated that EVs can transfer molecules between phylogenetically diverse species and can be used by parasites to alter the properties of the host environment. Whilst the concept of vesicle secretion and uptake is broad reaching, the molecular composition of these complexes is expected to be diverse based on the physiology and environmental niche of different organisms. Exosomes are one class of EVs originally defined based on their endocytic origin, as these derive from multivesicular bodies that then fuse with the plasma membrane releasing them into the extracellular environment. The term exosome has also been used to describe any small EVs recovered by high-speed ultracentrifugation, irrespective of origin since this is not always well characterized. Here, we use comparative global lipidomic analysis to examine the composition of EVs, which we term exosomes, that are secreted by the gastrointestinal nematode, Heligmosomoides polygyrus, in relation to exosomes secreted by cells of its murine host. Ultra-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) analysis reveals a 9- to 62-fold enrichment of plasmalogens, as well as other classes of ether glycerophospholipids, along with a relative lack of cholesterol and sphingomyelin (SM) in the nematode exosomes compared with those secreted by murine cells. Biophysical analyses of the membrane dynamics of these exosomes demonstrate increased rigidity in those from the nematode, and parallel studies with synthetic vesicles support a role of plasmalogens in stabilizing the membrane structure. These results suggest that nematodes can maintain exosome membrane structure and integrity through increased plasmalogens, compensating for diminished levels of other lipids, including cholesterol and SM. This work also illuminates the prevalence of plasmalogens in some EVs, which has not been widely reported and could have implications for the biochemical or immunomodulatory properties of EVs. Further comparative analyses such as those described here will shed light on diversity in the molecular properties of EVs that enable them to function in cross-species communication.

Homeostasis of phospholipids — The level of phosphatidylethanolamine tightly adapts to changes in ethanolamine plasmalogens

Ethanolamine plasmalogens constitute a group of ether glycerophospholipids that, due to their unique biophysical and biochemical properties, are essential components of mammalian cellular membranes. Their importance is emphasized by the consequences of defects in plasmalogen biosynthesis, which in humans cause the fatal disease rhizomelic chondrodysplasia punctata (RCDP). In the present lipidomic study, we used fibroblasts derived from RCDP patients, as well as brain tissue from plasmalogen-deficient mice, to examine the compensatory mechanisms of lipid homeostasis in response to plasmalogen deficiency. Our results show that phosphatidylethanolamine (PE), a diacyl glycerophospholipid, which like ethanolamine plasmalogens carries the head group ethanolamine, is the main player in the adaptation to plasmalogen insufficiency. PE levels were tightly adjusted to the amount of ethanolamine plasmalogens so that their combined levels were kept constant. Similarly, the total amount of polyunsaturated fatty acids (PUFAs) in ethanolamine phospholipids was maintained upon plasmalogen deficiency. However, we found an increased incorporation of arachidonic acid at the expense of docosahexaenoic acid in the PE fraction of plasmalogen-deficient tissues. These data show that under conditions of reduced plasmalogen levels, the amount of total ethanolamine phospholipids is precisely maintained by a rise in PE. At the same time, a shift in the ratio between ω-6 and ω-3 PUFAs occurs, which might have unfavorable, long-term biological consequences. Therefore, our findings are not only of interest for RCDP but may have more widespread implications also for other disease conditions, as for example Alzheimer's disease, that have been associated with a decline in plasmalogens.

Extraction of phospholipids from scallop by-product using supercritical CO2/alcohol mixtures

The objective was to produce phospholipid-enriched extracts from a new fishery by-product (scallop wastes) using supercritical fluid technology. A two-step fractionation scheme was used to improve the extraction selectivity by first deoiling the dried material by neat CO2 and secondly extracting phospholipids by CO2 plus ethanol. During this step, extracts were collected and quantified for their content in total lipids (by Folch extraction), phospholipids (by phosphorus nuclear magnetic resonance) and non-lipid components (by gravimetry). The influence of temperature (27–60 °C) and extracting fluid composition (15:85 to 50:50 w:w ethanol:CO2) on extraction kinetic and extract composition was analyzed. Propanol-2 was attempted as co-solvent as well. With ethanol, the highest content in phospholipids (58 g/100 g of extract) was obtained at 45 °C and 15 wt% of co-solvent, whereas propanol-2 was far more selective and led to an extract with a purity of 90 g/100 g of extract in phospholipids in conditions of 27 °C and 50 wt% of co-solvent. Compared to pure ethanol or conventional choroform:methanol extractions, CO2-based mixtures allowed for recovering extracts of phospholipids content higher than 35 g/100 g of lipids. Besides phosphatidylcholine, ether glycerophospholipids and phosphonolipids were detected in samples as well.

Serum choline plasmalogens—those with oleic acid in sn− 2—are biomarkers for coronary artery disease

BackgroundIdentifying risk factors is crucial for preventing cardiovascular events, but there are no widely accepted predictive biomarkers. In our previous study of Japanese asymptomatic cohorts, we performed global analysis of serum ether glycerophospholipids (Egp) molecular profiles, and found that choline plasmalogens (PlsCho; 1-O-alk-1′-enyl-2-acyl-sn-glycero-3-phosphocholine), particularly those containing oleic acid (18:1) in the sn−2 position, were strongly associated with a wide range of risk factors for metabolic syndrome/atherosclerosis. MethodsWe determined serum concentrations of Egp molecular species of coronary artery disease patients (n=50; 31 males and 19 females) by LC/MS/MS, and plasmalogen (Pls; 1-O-alk-1′-enyl-2-acyl-sn-glycerophospholipids) contents in lipoprotein fractions by HPLC using radioactive iodine. ResultsWe found that the serum concentrations of ether choline glycerophospholipids (EgpCho), particularly PlsCho, were not only significantly lower in males with significant coronary stenosis but also associated with atherosclerosis-related parameters, and their association was stronger than either high-density lipoprotein cholesterol or adiponectin. In addition, serum PlsCho containing 18:1 or linoleic acid (18:2) in sn−2 showed the highest correlations with a wide range of atherogenic parameters among PlsCho molecular species. ConclusionThese results verify our previous findings that serum PlsCho, particularly those containing 18:1 in sn−2, may serve as reliable biomarkers for atherosclerosis.

Serum choline plasmalogens, particularly those with oleic acid in sn-2, are associated with proatherogenic state

Serum plasmalogens (Pls) (1-O-alk-1'-enyl-2-acyl glycerophospholipids) are of particular interest for studies on metabolic disorders associated with oxidative stress and chronic inflammation. Serum levels of Pls are known to correlate positively with HDL-cholesterol (HDL-C); however, few studies have examined serum Pls molecular species in association with pathophysiological conditions and their clinical significance. To clarify these, we determined serum levels of individual ether glycerophospholipids in Japanese asymptomatic cohorts (n = 428; 362 male and 66 female subjects) by LC/MS/MS, and examined their correlations with clinical parameters. We found that the proportion of choline Pls (PlsCho) among total serum phospholipids was significantly lower in the male group over 40 years old and was associated with multiple risk parameters more strongly than HDL-C. The abundance of serum PlsCho with oleic acid (18:1) in sn-2 exhibited the strongest positive correlation with serum concentrations of adiponectin and HDL-C, while being inversely associated with waist circumference and the serum levels of TG and small dense LDL-cholesterol. The characterization of serum ether glycerophospholipids verified the specificity of PlsCho, particularly the ones with 18:1 in sn-2, as a sensitive biomarker for the atherogenic state.

Topogenesis and Homeostasis of Fatty Acyl-CoA Reductase 1

Peroxisomal fatty acyl-CoA reductase 1 (Far1) is essential for supplying fatty alcohols required for ether bond formation in ether glycerophospholipid synthesis. The stability of Far1 is regulated by a mechanism that is dependent on cellular plasmalogen levels. However, the membrane topology of Far1 and how Far1 is targeted to membranes remain largely unknown. Here, Far1 is shown to be a peroxisomal tail-anchored protein. The hydrophobic C terminus of Far1 binds to Pex19p, a cytosolic receptor harboring a C-terminal CAAX motif, which is responsible for the targeting of Far1 to peroxisomes. Far1, but not Far2, was preferentially degraded in response to the cellular level of plasmalogens. Experiments in which regions of Far1 or Far2 were replaced with the corresponding region of the other protein showed that the region flanking the transmembrane domain of Far1 is required for plasmalogen-dependent modulation of Far1 stability. Expression of Far1 increased plasmalogen synthesis in wild-type Chinese hamster ovary cells, strongly suggesting that Far1 is a rate-limiting enzyme for plasmalogen synthesis.

Ether Glycerophospholipids and Their Potential as Therapeutic Agents

Ether glycerophospholipids (GPLs) are a subclass of phospholipids, chemically characterized by the existence of an ether bond within the lipid molecules. Because ether GPLs are membrane structure components, they act as the wide-like resistance to membrane oxidation induced by chemical hypoxia and reactive oxygen species. The abnormal biosynthesis of ether GPLs in humans leads to the decreased supply of the critical lipids to various human cells, resulting in the alteration of the membrane lipid composition. Recent studies demonstrated that the level of docosahexaenoic acid (DHA) – containing ether molecular species of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in the Alzheimer’s brain significantly decreased. On the other hand, the deficiency of DHA and plateletactivating factor in human sperm causes infertility in men. We propose that the supplementation of DHA ether molecular species of GPLs may prevent and treat brain disorders, such as Alzheimer’s disease and autism, and infertility. The present review describes (1) procedures for the semi–synthesis of DHA – containing ether molecular species of PC and PE; (2) mass spectrometric methods for structurally identifying the lipids; (3) potential of DHA plasmanycholine species as lipid drugs for preventing and treating brain diseases and infertility; and (4) recommendation of marine oysters, monkfish liver and scallops based seafoods as DHA ether GPLs supplementation for the medical application. Keywords: Ether glycerophospholipids, docosahexaenoic acid, molecular nutrition, Alzheimer’s disease, autism, infertility.

ChemInform Abstract: Synthesis of New Ether Glycerophospholipids Structurally Related to Modulator.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and Antitumor Activity of Ether Glycerophospholipids Bearing a Carbamate Moiety at the sn‐2 Position: Selective Sensitivity Against Prostate Cancer Cell Lines

Analogues of 1-O-hexadecyl-sn-3-glycerophosphonocholine (compounds 1-4) or sn-3-glycerophosphocholine (compound 5) bearing a carbamate or dicarbamate moiety at the sn-2 position were synthesized and evaluated for their antiproliferative activity against cancer cells derived from a variety of tissues. Although all of the compounds are antiproliferative, surprisingly the carbamates (1 and 2) are more effective against the hormone-independent cell lines DU145 and PC3 than toward other cancer cell lines we examined. This selectivity was not observed with the dicarbamates (3 and 4). Phosphocholine carbamate analogue 5 is as effective against the prostate cancer cell lines as the corresponding phosphonocholine analogue 1. Cell death induced by 2'-(trimethylammonio)ethyl 4-hexadecyloxy-3(R)-N-methylcarbamoyl-1-butanephosphonate (carbamate analogue 2) appeared to be mediated by apoptosis, as assessed by caspase activation and loss of mitochondrial membrane potential. The in vivo activity of 2 was evaluated in a murine prostate cancer xenograft model. Oral and intravenous administration showed that 2 is effective in inhibiting the growth of PC3 tumors in Rag2M mice. Our studies show that the glycerolipid carbamates reported herein represent a class of prostate-cancer-selective cytotoxic agents.