6-Hydroxymethyl Indolizidin-2-one Amino Acid Synthesis, Conformational Analysis, and Biomedical Application as Dipeptide Surrogates in Prostaglandin-F2α Modulators.

6-Hydroxymethyl indolizidin-2-one amino acids were synthesized in 10 steps from l-serine by intramolecular ring opening of a symmetrical epoxide and lactam formation. X-ray analyses indicated the bicycles replicated ideal peptide type II' ß-turn central dihedral angle geometry. Inside a prostaglandin-F2α receptor modulator, the 6-hydroxymethyl analogue retained inhibitory activity on myometrial contractility.

Presence of multiple corpora lutea affects the luteolytic response to prostaglandin F2α in lactating dairy cows.

Since the 1970s, luteolytic doses used for synchronizing estrus in dairy cattle have remained unchanged. This study aimed to evaluate the dose-response effect of prostaglandin F2α (PGF2α), which is used for synchronizing estrus, and subsequent fertility in cows with two or more corpora lutea (CL). The study population consisted of 1,683 cows with a single CL (1CL), 501 cows with multiple CL receiving a single dose of PGF2α (2CL1), and 252 cows with multiple CL receiving a 1.5 × PGF2α dose (2CL1.5). Cows with a single CL (n = 1,245) showed estrus significantly (P < 0.01) earlier (3.01 ± 1.23 days; mean ± SD) than cows with multiple CL (n = 287; 3.33 ± 1.69 days). Using 1CL cows as reference, the odds ratio (OR) for the estrus response in 2CL1 cows was 0.13 (P < 0.0001), whereas the ORs for estrus response and pregnancy of 2CL1.5 cows were 1.8 (P = 0.0001) and 1.7 (P = 0.001), respectively. Based on the results for only the 2CL1 cows, the OR for the estrus response was 0.7 (P = 0.01) for cows producing ≥ 45 kg of milk at treatment, compared to the remaining cows producing < 45 kg of milk. Our results showed that the presence of multiple CL reduced the estrus response to that induced by a single PGF2α dose and milk production was inversely associated with this response, whereas an increased PGF2α dose improved the estrus response. Therefore, an increase in the standard PGF2α dose is recommended.

Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1.

Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.

Natural Products from Octocorals of the Genus Dendronephthya (Family Nephtheidae).

In this review, 170 natural substances, including steroid, diterpenoid, sesquiterpenoid, peptide, prostaglandin, base, chlorolipid, bicyclolactone, amide, piperazine, polyketide, glycerol, benzoic acid, glycyrrhetyl amino acid, hexitol, pentanoic acid, aminoethyl ester, octadecanone, alkaloid, and a 53-kD allergenic component from octocorals belonging to genus Dendronephthya, were listed. Some of these compounds displayed potential bioactivities.

Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde.

Prostaglandins have been attractive targets in total synthesis for over 50 years, resulting in the development of new synthetic strategies and methodologies that have served the broader chemical community. However, these molecules are not just of academic interest, a number of prostaglandin analogues are used in the clinic, and some are even on the WHO list of essential medicines. In this personal account, we describe our own approach to the family of prostaglandins, which centers around the synthesis of a key enal intermediate, formed from the l-proline catalysed dimerization of succinaldehyde. We highlight the discovery and further optimization of this key reaction, its scale up, and subsequent application to a range of prostaglandins.

Simultaneous Determination of Prostaglandin and Hormones in Excreta of Trogopterus xanthipes.

The excreta of Trogopterus xanthipes (also called Wulingzhi in Chinese, WLZ) is a well-known traditional Chinese medicine used for the treatment of irregular menstruation in clinic. Few reports are available on the chemical profiling of WLZ. In this work, qualitative and quantitative analyses of endogenous prostaglandin and hormones in WLZ were performed using UHPLC-orbitrap-MSn. In total, 48 compounds were identified in urine of T. xanthipes. Furthermore, the contents of four target compounds were simultaneously quantitated in 20 batches of samples by UPLC-MS/MS. The quantitative method showed a good linear correlation (R > 0.995) in a wide range for each compound. The method had a high sensitivity with LOD (0.5-1.0 ng/mL) and LOQ (1.0-2.5 ng/mL). The intra- and inter-day precisions were < 9.17 (RSD %), and repeatability and stability were < 6.14 (RSD %). The recovery of the analytes varied between 85.8% and 97.3% at three different concentrations. The present integrated qualitative and quantitative assessment of WLZ provides an evaluation strategy to assess the constituent in traditional Chinese medicine.

Identification of Prostaglandin Pathway in Dinoflagellates by Transcriptome Data Mining.

Dinoflagellates, a major class of marine eukaryote microalgae composing the phytoplankton, are widely recognised as producers of a large variety of toxic molecules, particularly neurotoxins, which can also act as potent bioactive pharmacological mediators. In addition, similarly to other microalgae, they are also good producers of polyunsaturated fatty acids (PUFAs), important precursors of key molecules involved in cell physiology. Among PUFA derivatives are the prostaglandins (Pgs), important physiological mediators in several physiological and pathological processes in humans, also used as "biological" drugs. Their synthesis is very expensive because of the elevated number of reaction steps required, thus the search for new Pgs production methods is of great relevance. One possibility is their extraction from microorganisms (e.g., diatoms), which have been proved to produce the same Pgs as humans. In the present study, we took advantage of the available transcriptomes for dinoflagellates in the iMicrobe database to search for the Pgs biosynthetic pathway using a bioinformatic approach. Here we show that dinoflagellates express nine Pg-metabolism related enzymes involved in both Pgs synthesis and reduction. Not all of the enzymes were expressed simultaneously in all the species analysed and their expression was influenced by culturing conditions, especially salinity of the growth medium. These results confirm the existence of a biosynthetic pathway for these important molecules in unicellular microalgae other than diatoms, suggesting a broad diffusion and conservation of the Pgs pathway, which further strengthen their importance in living organisms.

The chemistry, biology and pharmacology of the cyclopentenone prostaglandins.

The cyclopentenone prostaglandins (CyPGs) are a small group compounds that are a subset of the eicosanoid superfamily, which are metabolites of arachidonic acid as well as other polyunsaturated fatty acids. The CyPGs are defined by a structural feature, namely, a five-membered carbocyclic ring containing an alfa-beta unsaturated keto group. The two most studied members are PGA2 and 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2); other less studied members are PGA1, Δ12-PGJ2, and PGJ2. They are involved in a number of biological activities including the ability to resolve chronic inflammation and the growth and survival of cells, particularly those of cancerous or neurological origin. Also, they can activate the prostaglandin DP2 receptor as well as the ligand-dependent transcription factor PPAR-gamma. Their ability to promote the resolution of chronic inflammation makes it of particular interest to have a good understanding of their actions. Since their discovery, the literature on the CyPGs has greatly expanded both in size and in scope; these reports are covered in the current review.

Aspects of Prostaglandin Glycerol Ester Biology.

The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O2 into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much work has been done showing that COX-2 will perform this reaction on several different AA-containing molecules, most importantly, the endocannabinoid 2-arachidonoylglycerol (2-AG). The products of 2-AG oxygenation, prostaglandin glycerol esters (PG-Gs), are analogous to canonical prostaglandins. This chapter reviews the literature detailing the production, metabolism, and bioactivity of these compounds, as well as their detection in intact animals.

Assessment of lipid peroxidation and artificial neural network models in early Alzheimer Disease diagnosis.

OBJECTIVE: Lipid peroxidation constitutes a molecular mechanism involved in early Alzheimer Disease (AD) stages, and artificial neural network (ANN) analysis is a promising non-linear regression model, characterized by its high flexibility and utility in clinical diagnosis. ANN simulates neuron learning procedures and it could provide good diagnostic performances in this complex and heterogeneous disease compared with linear regression analysis. DESIGN AND METHODS: In our study, a new set of lipid peroxidation compounds were determined in urine and plasma samples from patients diagnosed with early Alzheimer Disease (n = 70) and healthy controls (n = 26) by means of ultra-performance liquid chromatography coupled with tandem mass-spectrometry. Then, a model based on ANN was developed to classify groups of participants. RESULTS: The diagnostic performances obtained using an ANN model for each biological matrix were compared with the corresponding linear regression model based on partial least squares (PLS), and with the non-linear (radial and polynomial) support vector machine (SVM) models. Better accuracy, in terms of receiver operating characteristic-area under curve (ROC-AUC), was obtained for the ANN models (ROC-AUC 0.882 in plasma and 0.839 in urine) than for PLS and SVM models. CONCLUSION: Lipid peroxidation and ANN constitute a useful approach to establish a reliable diagnosis when the prognosis is complex, multidimensional and non-linear.

Prostaglandins in Marine Organisms: A Review.

Prostaglandins (PGs) are lipid mediators belonging to the eicosanoid family. PGs were first discovered in mammals where they are key players in a great variety of physiological and pathological processes, for instance muscle and blood vessel tone regulation, inflammation, signaling, hemostasis, reproduction, and sleep-wake regulation. These molecules have successively been discovered in lower organisms, including marine invertebrates in which they play similar roles to those in mammals, being involved in the control of oogenesis and spermatogenesis, ion transport, and defense. Prostaglandins have also been found in some marine macroalgae of the genera Gracilaria and Laminaria and very recently the PGs pathway has been identified for the first time in some species of marine microalgae. In this review we report on the occurrence of prostaglandins in the marine environment and discuss the anti-inflammatory role of these molecules.

The development of a silicone vaginal ring with a prostaglandin analogue for potential use in the treatment of canine reproductive disorders.

In veterinary medicine, vaginal rings (VRs) are rarely used. However, there are diseases of female dogs' reproductive system which represent a suitable possibility for their usage. An example of such a disease is canine pyometra which can be treated by lipophilic prostaglandin drugs, unfortunately with harmful side effects after systemic administration. The aim of the study was to prove that the matrix VR based on silicone and channel-forming substance can be successfully used as a carrier for a three-day delivery of prostaglandin E2 (PGE2). Based on an in-vitro release study, an optimum channel-forming substance and its concentration were selected. The results were implemented during the construction of VR from the medical grade silicone DDU-4840 with PGE2 (5 mg). Glucose anhydrous in the 30% concentration was chosen as the most functional channel-forming substance due to synergism of osmotic activity and solubility. The DDU-VR containing PGE2 and 30% of glucose anhydrous exhibited excellent mechanical characteristics and ensured 29% drug release through water-filled channels in first-order kinetic manner. This is eight times higher than a sample without glucose where molecular diffusion through the silicone matrix was dominating the release mechanism. Moreover, drug-free VRs were tested for mechanical resistance and the design of removal thread.

Lipidomic methodologies for biomarkers of chronic inflammation in nutritional research: ω-3 and ω-6 lipid mediators.

The evolutionary history of hominins has been characterized by significant dietary changes, which include the introduction of meat eating, cooking, and the changes associated with plant and animal domestication. The Western pattern diet has been linked with the onset of chronic inflammation, and serious health problems including obesity, metabolic syndrome, and cardiovascular diseases. Diets enriched with ω-3 marine PUFAs have revealed additional improvements in health status associated to a reduction of proinflammatory ω-3 and ω-6 lipid mediators. Lipid mediators are produced from enzymatic and non-enzymatic oxidation of PUFAs. Interest in better understanding the occurrence of these metabolites has increased exponentially as a result of the growing evidence of their role on inflammatory processes, control of the immune system, cell signaling, onset of metabolic diseases, or even cancer. The scope of this review has been to highlight the recent findings on: a) the formation of lipid mediators and their role in different inflammatory and metabolic conditions, b) the direct use of lipid mediators as antiinflammatory drugs or the potential of new drugs as a new therapeutic option for the synthesis of antiinflammatory or resolving lipid mediators and c) the impact of nutritional interventions to modulate lipid mediators synthesis towards antiinflammatory conditions. In a second part, we have summarized methodological approaches (Lipidomics) for the accurate analysis of lipid mediators. Although several techniques have been used, most authors preferred the combination of SPE with LC-MS. Advantages and disadvantages of each method are herein addressed, as well as the main LC-MS difficulties and challenges for the establishment of new biomarkers and standardization of experimental designs, and finally to deepen the study of mechanisms involved on the inflammatory response.

Concise Syntheses of Δ12-Prostaglandin J Natural Products via Stereoretentive Metathesis.

Δ12-Prostaglandin J family is recently discovered and has potent anticancer activity. Concise syntheses of four Δ12-prostaglandin J natural products (7-8 steps in the longest linear sequences) are reported, enabled by convergent stereoretentive cross-metathesis. Exceptional control of alkene geometry was achieved through stereoretention.

A Unique Collision-Induced Dissociation Reaction of Cholamine Derivatives of Certain Prostaglandins.

Prostaglandins (PGs) are biologically active metabolites of arachidonic acid containing 20 carbon atoms, a cyclic moiety, and two side chains (A and B) in common. The bioassay of PGs requires high sensitivity because of their low concentration in tissues and blood and has usually been carried out by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the negative ion mode. Chemical derivatization of PG carboxylic acid groups to introduce positive charge-carrying groups is an established strategy to improve the sensitivity and selectivity of such assays. In this study, we exploited this approach for structural identification of a series of PGs using cholamine derivatization through an amidation reaction. However, we observed that collision-induced dissociation of these derivatives gave rise to unexpected product ions that we postulated were formed by unique long-range intramolecular reactions resulting in dehydration of the B chain accompanied by fragmentation of the A chain through an unusual Hofmann rearrangement. Evidence for the proposed mechanism is presented based on ESI-MS/MS and high resolution mass spectrometry studies of cholamine derivatives of PGE1, PGE2, PGD2, PGI2, and C-17 methyl deuterium-labeled limaprost. Graphical Abstract.

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12 -Prostaglandin J3.

Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi-gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ12 -prostaglandin J3 , a compound with known anti-leukemic properties.

Lipocalin-Type Prostaglandin D Synthase Is a Novel Phytocannabinoid-Binding Protein.

Lipocalin-type prostaglandin D synthase (L-PGDS; EC:5.3.99.2) is an enzyme with dual functional roles as a prostaglandin D2 -synthesizing enzyme and as an extracellular transporter for diverse lipophilic compounds in the cerebrospinal fluid (CSF). Transport of hydrophobic endocannabinoids is mediated by serum albumin in the blood and intracellularly by the fatty acid binding proteins, but no analogous transport mechanism has yet been described in CSF. L-PGDS has been reported to promiscuously bind a wide variety of lipophilic ligands and is among the most abundant proteins found in the CSF. Here, we examine the binding of several classes of endogenous and synthetic ligands to L-PGDS. Endocannabinoids exhibited low affinity toward L-PGDS, while cannabinoid metabolites and synthetic cannabinoids displayed higher affinities for L-PGDS. These results indicate that L-PGDS is unlikely to function as a carrier for endocannabinoids in the CSF, but it may bind and transport a subset of cannabinoids.

The cysteine residue of glial fibrillary acidic protein is a critical target for lipoxidation and required for efficient network organization.

The type III intermediate filament protein glial fibrillary acidic protein (GFAP) contributes to the homeostasis of astrocytes, where it co-polymerizes with vimentin. Conversely, alterations in GFAP assembly or degradation cause intracellular aggregates linked to astrocyte dysfunction and neurological disease. Moreover, injury and inflammation elicit extensive GFAP organization and expression changes, which underline reactive gliosis. Here we have studied GFAP as a target for modification by electrophilic inflammatory mediators. We show that the GFAP cysteine, C294, is targeted by lipoxidation by cyclopentenone prostaglandins (cyPG) in vitro and in cells. Electrophilic modification of GFAP in cells leads to a striking filament rearrangement, with retraction from the cell periphery and juxtanuclear condensation in thick bundles. Importantly, the C294S mutant is resistant to cyPG addition and filament disruption, thus highlighting the critical role of this residue as a sensor of oxidative damage. However, GFAP C294S shows defective or delayed network formation in GFAP-deficient cells, including SW13/cl.2 cells and GFAP- and vimentin-deficient primary astrocytes. Moreover, GFAP C294S does not effectively integrate with and even disrupts vimentin filaments in the short-term. Interestingly, short-spacer bifunctional cysteine crosslinking produces GFAP-vimentin heterodimers, suggesting that a certain proportion of cysteine residues from both proteins are spatially close. Collectively, these results support that the conserved cysteine residue in type III intermediate filament proteins serves as an electrophilic stress sensor and structural element. Therefore, oxidative modifications of this cysteine could contribute to GFAP disruption or aggregation in pathological situations associated with oxidative or electrophilic stress.

Targeting therapeutics to bone by conjugation with bisphosphonates.

Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily.

Rabbit plasma metabolomic analysis of Nitroproston®: a multi target natural prostaglandin based-drug.

INTRODUCTION: Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis). OBJECTIVES: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo. METHODS: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n = 6 in each group). Untargeted (5880 initial features; 1869 negative-4011 positive ion peaks; UPLC-IT-TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC-QQQ-MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 min after administration. RESULTS: PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e., cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate D-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadipic acid and uric acid increased (p < 0.05 AUCROC curve > 0.75) after treatment. Purines (i.e., xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids L-tryptophan and L-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others. CONCLUSION: Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites (i.e., guanine, adenine, cortisol, cortisone and aspartate) involved in purine metabolism, urea and ammonia biological cycles, steroidogenesis, among other pathways. Suggested mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.