In 2021, novel oxylipins plasmodiophorol A-C were identified as products of the hydroperoxide bicyclase activity of CYP50918A1 from Plasmodiophora brassicae (Rhizaria, SAR). Here, we report the first total syntheses of plasmodiophorol A and C in 12 and 13 steps, respectively, starting from chiral tetrahydro-1H-cyclopentafuranone. Key transformations included enzymatic desymmetrization, epimerization, and diastereoselective Grignard addition. Notably, during the synthesis of plasmodiophorol C, we also generated and structurally characterized a previously unknown compound. These synthetic routes provide reliable access to plasmodiophorols A and C, offering valuable standards for probing their biosynthetic pathways and facilitating their identification in marine biomasses. This work lays the foundation for further chemical and biological studies of these unique oxylipins.

Hybridalactone, agardhilactone, ecklonialactones, eiseniachlorides, and egregiachlorides, isolated from the marine macroalgae such as Laurencia hybrida, Agardhiella subulate, Ecklonia stolonifera, Eisenia bicyclis, and Egregia menziesii, are biosynthesized through a lipoxygenase (LOX)-mediated oxidative pathway involving polyunsaturated fatty acids (PUFAs). This enzymatic process generates hydroperoxide intermediates, which subsequently undergo regio- and stereospecific transformations to yield structurally diverse oxygenated metabolites, including plasmodiophorols and ectocarpins. These compounds are characterized by a conserved vinylcyclopentyl moiety, a structural hallmark critical to elucidating the mechanistic underpinnings of oxylipin biosynthesis in marine algae. The elucidation of these biosynthetic pathways enhances understanding of oxylipin enzymatic regulation and chemical diversity, while underscoring their ecological roles as signaling or defense molecules in marine ecosystems. Their unique structures and bioactivities offer potential for pharmacological and biotechnological applications, including novel bioactive agents. Investigating their production, structural complexity, and functionality is crucial for advancing marine natural product chemistry and exploring their ecological and industrial significance.

A total enantioselective synthesis of ectocarpin A, an oxylipin identified through the first hydroperoxide bicyclase activity of CYP5164A3 in brown algae, has been successfully completed in 12 steps starting from tetrahydro-1H-cyclopentafuranone. Key transformations include the creation of the chiral tetrahydro-1H-cyclopentafuranone, a diastereoselective epoxidation, an enzymatic desymmetrization of a 1,4-diol, an epimerization, and both Wittig and Julia-Kocienski olefinations to build the carbon framework of ectocarpin A.

Pistachio (Pistacia vera L.) is a drought-tolerant species grown under the semiarid conditions of the Mediterranean basin. For this reason, it is essential to make an exhaustive quantification of yield and quality benefits of the kernels because the regulated deficit irrigation will allow significant water savings with a minimum impact on yield while improving kernel quality. The goal of this scientific work was to study the influence of the rootstock, water deficit during pit hardening, and kernel roasting on pistachio (P. vera, cv. Kerman) fruit yield, fruit size, and kernel content of fatty acids phytoprostanes (PhytoPs) and phytofurans (PhytoFs) for the first time. Water stress during pit hardening did not affect the pistachio yield. The kernel cultivar showed a lower oleic acid and a higher linoleic acid contents than other cultivars. Kernels from plants grafted on the studied rootstocks showed very interesting characteristics. P. integerrima led to the highest percentage of monounsaturated fatty acids. Regarding the plant oxylipins, P. terebinthus led to the highest contents of PhytoPs and PhytoFs (1260 ng/100 g and 16.2 ng/100 g, respectively). In addition, nuts from trees cultivated under intermediate water deficit during pit hardening showed increased contents of the 9-series F1-phytoprostanes and ent-16(RS)-9-epi-ST-Δ14-10-phytofuran. However, roasting of pistachios led to PhytoP degradation. Therefore, plant cultivar, deficit irrigation, rootstock, and roasting must be considered to enhance biosynthesis of these secondary metabolites. New tools using agricultural strategies to produce hydroSOS pistachios have been opened thanks to the biological properties of these prostaglandin-like compounds linking agriculture, nutrition, and food science technology for further research initiatives.

BACKGROUND: The effect of regulated deficit irrigation (RDI) on the phytoprostane (PhytoP) content in extra virgin olive (Olea europaea L., cv. Cornicabra) oil (EVOO) was studied. During the 2012 and 2013 seasons, T0 plants were irrigated at 100% ETc, while T1 and T2 plants were irrigated avoiding water deficit during phases I and III of fruit growth and saving water during the non-critical phenological period of pit hardening (phase II), developing amore severewater deficit in T2 plants. In 2013, a fourth treatment (T3) was also performed, which was similar to T2 except that water saving was from the beginning of phase II to 15 days after the end of phase II. RESULTS: 9-F1t-PhytoP, 9-epi-9-F1t-PhytoP, 9-epi-9-D1t-PhytoP, 9-D1t-PhytoP, 16-B1-PhytoP and 9-L1-PhytoP were present in Cornicabra EVOO, and their contents increased in the EVOO fromRDI plants. CONCLUSION: Deficit irrigation during pit hardening or for a further period of 2 weeks thereafter to increase irrigation water saving is clearly critical for EVOO composition because of the enhancement of free PhytoPs, which have potential beneficial effects on human health. The response of individual free PhytoPs to changes in plant water status was not as perceptible as expected, preventing their use as biomarkers of water stress.

We have evidence that F2-isoprostanes (F2-IsoPs) regulate the release of excitatory neurotransmitters in isolated bovine retina. Although 5-F3-IsoPs are generated in mammals, in vivo, their pharmacological actions on neurotransmitter release remain unknown. In this study, we investigated the effect of 5-epi-5-F3t-IsoP on K+-evoked [3H]d-aspartate release in isolated bovine retina using the superfusion method. Furthermore, we examined the role of arachidonic acid metabolites in the regulation of the neurotransmitter release by this novel IsoP. In the concentration range, 0.01 nM–0.1 µM, 5-epi-5-F3t-IsoP inhibited K+-evoked [3H]d-aspartate release in a concentration-dependent manner, achieving a maximum inhibition of 46.9 % at 0.1 µM (IC30 = 1 nM). The prostanoid receptor antagonists, AH 6809 (EP1–3/DP; 10 µM), SC 51322 (EP1; 10 µM) and SC 19220 (EP1; 1 µM) partially reversed 5-epi-5-F3t-IsoP-mediated inhibition of K+-induced [3H]d-aspartate release. Pretreatment of retinal tissues with the cyclooxygenase (COX) inhibitor, flurbiprofen (3 μM) unmasked a biphasic action of 5-epi-5-F3t-IsoP that was inhibitory at lower (0.1–10 pM) and stimulatory at higher concentrations (≥0.1 nM). The prostanoid pathway antagonists, BAY-u3405 (10 μM; TP/DP-receptors), SQ 29548 (10 μM; TP-receptor) and ozagrel (10 μM; Tx-synthase inhibitor) abolished the stimulatory action of the 5-epi-5-F3t-IsoP (0.1 μM) on neurotransmitter release. In conclusion, 5-epi-5-F3t-IsoP attenuates K+-induced [3H]d-aspartate release in a concentration-dependent manner by mechanisms that are partially dependent on activation of pre-junctional prostanoid EP1-receptors. Moreover, blockade of the COX-pathway unmasks a biphasic action for 5-epi-5-F3t-IsoP that is inhibitory at low concentrations and stimulatory at higher concentrations. Products of the thromboxane synthase pathway may partially account for the stimulatory action of this F3-IsoP on isolated bovine retina.

Oxidative damage has been reported in Rett syndrome (RTT), a pervasive development disorder mainly caused up to 95% of cases by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. We have recently synthesized F(2)-Dihomo-isoprostanes (F(2)-Dihomo-IsoP), peroxidation products from adrenic acid (C22:4 n - 6, AdA), a known component of myelin, and tested the potential value of F(2)-Dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation, and disease progression. F(2)-Dihomo-IsoPs were determined by a gas chromatography/negative ion chemical ionization tandem mass spectrometry. The ent-7(RS)-F(2t)-Dihomo-IsoP and 17-F(2t)-Dihomo-IsoP were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M - 181](-) precursor ions (m/z 597) produced from both the derivatized ent-7(RS)-F(2t)-Dihomo-IsoP and 17-F(2t)-Dihomo-IsoP. Average plasma F(2)-Dihomo-IsoP levels in RTT were about 1 order of magnitude higher than in healthy controls, being higher in typical RTT as compared to RTT variants, with a remarkable increase of about 2 orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. These data indicate for the first time that quantification of F(2)-Dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT.

Polyunsaturated fatty acids (PUFA) are important constituents in all eukaryotic organisms, contributing to the structural integrity of biological membranes and serving as precursors for enzymatically-generated local hormones. In addition to these functions, PUFA can generate by a free radical-initiated mechanism, key products which participate in a variety of pathophysiological processes. In particular, free radical-catalyzed peroxidation of PUFA leads to in vivo formation of isoprostanes (IsoP), neuroprostanes (NeuroP), and phytoprostanes (PhytoP) which display a wide range of biological actions. IsoP are now the most reliable indicators of oxidative stress in humans. In this review, we will discuss some advances in our knowledge regarding two cyclic PUFA derivatives, IsoP and PhytoP, and how their biological roles may be clarified through new approaches based on analytical and synthetic organic chemistry.

In animals and plants, fatty acids with at least three double bonds can be oxidized to prostaglandin-like compounds via enzymatic and non-enzymatic pathways. The most common fatty acid precursor in mammals is arachidonic acid (C20:4) (AA) which can be converted through the cyclooxygenase pathway to a series of prostaglandins (PG). Non-enzymatic cyclization of arachidonate yields a series of isoprostanes (IsoP) which comprises all PG (minor compounds) as well as PG isomers that cannot be formed enzymatically. In contrast, in plants, alpha-linolenic acid (C18:3) (ALA) is the most common substrate for the allene oxide synthase pathway leading to the jasmonate (JA) family of lipid mediators. Non-enzymatic oxidation of linolenate leads to a series of C18-IsoPs termed dinor IsoP or phytoprostanes (PP). PP structurally resemble JA but cannot be formed enzymatically. We will give an overview of the biological activity of the different classes of PP and also discuss their analytical applications and the strategies developed so far for the total synthesis of PP, depending on the synthetic approaches according to the targets and which key steps serve to access the natural products.

The first synthesis of the two enantiomers of phytoprostane F1 methyl ester 1 and 2 is described using the syn–anti–syn alcoxy ester 3 as starting material.

We report a new route to F-2t-IsoP (formerly named 8-epi-PGF(2alpha)) using a biomimetic radical cyclization of a highly functionalized C20 precursor. The strategy employed gives a beta-hydroxy free radical followed by molecular oxygen trapping, which is an unusual method for quenching carbon free radicals. We observed the formation of unique diastereoisomers (15R)- and (15S)-F-2t-IsoP. This result is consistent with a strong stereoelectronic control associated with a steric effect initiated by the side chains alpha and omega on the cyclopentane ring.