Pentalenic Acid Research Articles

Discovery of plasma biomarkers for Parkinson's disease diagnoses based on metabolomics and lipidomics

Parkinson's disease (PD) is an aging-associated neurodegenerative movement disorder with increasing morbidity and mortality rates. The current gold standard for diagnosing PD is clinical evaluation, which is often challenging and inaccurate. Metabolomics and lipidomics approaches have been extensively applied because of their potential in discovering valuable biomarkers for medical diagnostics. Here, we used comprehensive untargeted metabolomics and lipidomics methodologies based on liquid chromatography-mass spectrometry to evaluate metabolic abnormalities linked with PD. Two well-characterized cohorts of 288 plasma samples (143 PD patients and 145 control subjects in total) were used to examine metabolic alterations and identify diagnostic biomarkers. Unbiased multivariate and univariate studies were combined to identify the promising metabolic signatures, based on which the discriminant models for PD were established by integrating multiple machine learning algorithms. A 6-biomarker predictive model was constructed based on the omics profile in the discovery cohort, and the discriminant performance of the biomarker panel was evaluated with an accuracy over 81.6% both in the discovery cohort and validation cohort. The results indicated that PC (40:7), eicosatrienoic acid were negatively correlated with severity of PD, and pentalenic acid, PC (40:6p) and aspartic acid were positively correlated with severity of PD. In summary, we developed a multi-metabolite predictive model which can diagnose PD with over 81.6% accuracy based on this unique metabolic signature. Future clinical diagnosis of PD may benefit from the biomarker panel reported in this study.

Dual Induction of New Microbial Secondary Metabolites by Fungal Bacterial Co-cultivation.

The frequent re-isolation of known compounds is one of the major challenges in drug discovery. Many biosynthetic genes are not expressed under standard culture conditions, thus limiting the chemical diversity of microbial compounds that can be obtained through fermentation. On the other hand, the competition during co-cultivation of two or more different microorganisms in most cases leads to an enhanced production of constitutively present compounds or an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain under different fermentation conditions. Herein, we report the dual induction of newly detected bacterial and fungal metabolites by the co-cultivation of the marine-derived fungal isolate Aspergillus fumigatus MR2012 and two hyper-arid desert bacterial isolates Streptomyces leeuwenhoekii strain C34 and strain C58. Co-cultivation of the fungal isolate MR2012 with the bacterial strain C34 led to the production of luteoride D, a new luteoride derivative and pseurotin G, a new pseurotin derivative in addition to the production of terezine D and 11-O-methylpseurotin A which were not traced before from this fungal strain under different fermentation conditions. In addition to the previously detected metabolites in strain C34, the lasso peptide chaxapeptin was isolated under co-culture conditions. The gene cluster for the latter compound had been identified through genome scanning, but it had never been detected before in the axenic culture of strain C34. Furthermore, when the fungus MR2012 was co-cultivated with the bacterial strain C58, the main producer of chaxapeptin, the titre of this metabolite was doubled, while additionally the bacterial metabolite pentalenic acid was detected and isolated for the first time from this strain, whereas the major fungal metabolites that were produced under axenic culture were suppressed. Finally, fermentation of the MR2012 by itself led to the isolation of the new diketopiperazine metabolite named brevianamide X.

Pentalenic acid is a shunt metabolite in the biosynthesis of the pentalenolactone family of metabolites: hydroxylation of 1-deoxypentalenic acid mediated by CYP105D7 (SAV_7469) of Streptomyces avermitilis

Pentalenic acid (1) has been isolated from many Streptomyces sp. as a co-metabolite of the sesquiterpenoid antibiotic pentalenolactone and related natural products. We have previously reported the identification of a 13.4-kb gene cluster in the genome of Streptomyces avermitilis implicated in the biosynthesis of the pentalenolactone family of metabolites consisting of 13 open reading frames. Detailed molecular genetic and biochemical studies have revealed that at least seven genes are involved in the biosynthesis of the newly discovered metabolites, neopentalenoketolactone, but no gene specifically dedicated to the formation of pentalenic acid (1) was evident in the same gene cluster. The wild-type strain of S. avermitilis, as well as its derivatives, mainly produce pentalenic acid (1), together with neopentalenoketolactone (9). Disruption of the sav7469 gene encoding a cytochrome P450 (CYP105D7), members of which class are associated with the hydroxylation of many structurally different compounds, abolished the production of pentalenic acid (1). The sav7469-deletion mutant derived from SUKA11 carrying pKU462∷ptl-clusterΔptlH accumulated 1-deoxypentalenic acid (5), but not pentalenic acid (1). Reintroduction of an extra-copy of the sav7469 gene to SUKA11 Δsav7469 carrying pKU462∷ptl-clusterΔptlH restored the production of pentalenic acid (1). Recombinant CYP105D7 prepared from Escherichia coli catalyzed the oxidative conversion of 1-deoxypentalenic acid (5) to pentalenic acid (1) in the presence of the electron-transport partners, ferredoxin (Fdx) and Fdx reductase, both in vivo and in vitro. These results unambiguously demonstrate that CYP105D7 is responsible for the conversion of 1-deoxypentalenic acid (5) to pentalenic acid (1), a shunt product in the biosynthesis of the pentalenolactone family of metabolites.

ChemInform Abstract: Application of the Pauson-Khand Reaction to the Synthesis of Pentalenic Acid.

Abstract A substituted penthynylcyclopentene precursor for the synthesis of pentalenic acid by intramolecular Pauson–Khand cycloaddition reaction has been prepared in high yield. Reaction with Co2(CO)8 produces triquinane econes in an overall yield of 33%. Three of the four possible stereoisomeric products are formed, with two of them, making up ca. 80% of the product mixture, possessing the necessary exo-methyl stereochemistry at C-9 for further elaboration into pentalenic acid. A formal synthesis of the latter was completed by reduction of one of the enone isomers into a ketone which had previously been carried on to the natural product.

ChemInform Abstract: Highly Stereo- and Regiocontrolled Cyclopentannulation via Allylphosphonate Conjugate Addition and Hydroboration-Oxidation- Elimination. Synthesis of Pentalenic Acid with Virtually Complete Stereo- and Regiocontrol.

ChemInform Abstract: Highly Stereo- and Regiocontrolled Cyclopentannulation via Allylphosphonate Conjugate Addition and Hydroboration-Oxidation- Elimination. Synthesis of Pentalenic Acid with Virtually Complete Stereo- and Regiocontrol.

ChemInform Abstract: Zipper-Mode Cascade Carbometallation for Construction of Polycyclic Structures

A novel concept for the synthesis of polycyclic compounds via zipper-mode cyclic carbometallation reactions has been introduced. The Zr-promoted bicyclization-carbonylation of enynes can be highly diastereoselective, leading to the formation of stereoisomerically homogeneous bicyclic ketones. The reaction has been applied to a total synthesis of pentalenic acid with essentially complete control of stereo- and regiochemistry. In contrast to the Za-promoted methodology, whose applicability is limited to bicyclization, cyclic carbopalladation can repeat itself to produce three or more rings in one step, provided that P-elimination or other decomposition paths are not available. Alkynes and 1,l-disubstituted alkenes can serve as relay functionalities. With 1,l-disubstituted alkenes, however, the regiochemistry of cyclization can be complicated by cyclopropanation. Efforts have been made to delineate the scope of cyclopropanation. Finally, cyclic acylpalladation followed by intramolecular trapping by 0-enolates can give enol lactones via bicyclization. This bicyclization process has been applied to an expeditious synthesis of a tricyclic intermediate for a promising anti-ulcer agent U-68,215.

ChemInform Abstract: Nickel-Catalyzed Cyclizations of Enoate Equivalents: Application to the Synthesis of Angular Triquinanes.

Unsaturated acyloxazolidinones and α‘-silyloxy enones were found to be effective substrates in nickel-catalyzed organozinc-promoted cyclizations. Both groups served as convenient enoate equivalents, whereas methyl enoates themselves were inefficient substrates. A five-step procedure for the conversion of dimethylcyclopentenone into a highly functionalized angular triquinane was developed utilizing this observation. The key step of the procedure involves a nickel-catalyzed reductive cyclization/Dieckmann condensation sequence involving a cyclic enone tethered to an unsaturated acyloxazolidinone or α‘-silyloxy enone. The method was applied in a formal synthesis of pentalenene, pentalenic acid, and deoxypentalenic acid.

A Gene Cluster for Biosynthesis of the Sesquiterpenoid Antibiotic Pentalenolactone in Streptomyces avermitilis

Streptomyces avermitilis, an industrial organism responsible for the production of the anthelminthic avermectins, harbors a 13.4 kb gene cluster containing 13 unidirectionally transcribed open reading frames corresponding to the apparent biosynthetic operon for the sesquiterpene antibiotic pentalenolactone. The advanced intermediate pentalenolactone F, along with the shunt metabolite pentalenic acid, could be isolated from cultures of S. avermitilis, thereby establishing that the pentalenolactone biosynthetic pathway is functional in S. avermitilis. Deletion of the entire 13.4 kb cluster from S. avermitilis abolished formation of pentalenolactone metabolites, while transfer of the intact cluster to the pentalenolactone nonproducer Streptomyces lividans 1326 resulted in production of pentalenic acid. Direct evidence for the biochemical function of the individual biosynthetic genes came from expression of the ptlA gene (SAV2998) in Escherichia coli. Assay of the resultant protein established that PtlA is a pentalenene synthase, catalyzing the cyclization of farnesyl diphosphate to pentalenene, the parent hydrocarbon of the pentalenolactone family of metabolites. The most upstream gene in the cluster, gap1 (SAV2990), was shown to correspond to the pentalenolactone resistance gene, based on expression in E. coli and demonstration that the resulting glyceraldehyde-3-phosphate dehydrogenase, the normal target of pentalenolactone, was insensitive to the antibiotic. Furthermore, a second GAPDH isozyme (gap2, SAV6296) has been expressed in E. coli and shown to be inactivated by pentalenolactone.

Syntheses of Biologically Active Natural Products and Leading Compounds for New Pharmaceuticals Employing Effective Construction of a Polycyclic Skeleton

Cascade reactions are useful methods for the construction of polycyclic skeletons, which are important cores for biological activities. A variety of cascade reactions carried out under multiple reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions, have been investigated. Culmorin, pentalenene, pentalenic acid, deoxypentalenic acid, longiborneol, cedrandiol, 8,14-cedranoxide, atisirene, atisine, and estrane-type steroids were synthesized via the intramolecular double Michael reaction. Aza double Michael reaction was applied to the syntheses of tylophorine, epilupinine, tacamonine, and paroxetine. Furthermore, sequential Michael and aldol reactions were performed in both intramolecular and intermolecular manners, leading to the formation of polycyclic compounds fused to a four-membered ring. Synthesis of paesslerin A utilizing a multicomponent cascade reaction revealed an error in the proposed structure. Unique cascade reactions carried out under radical and transition metal-catalyzed reaction conditions were also investigated. With the combination of several cascade reactions, serofendic acids and methyl 7beta-hydroxykaurenoate, both of which have neuroprotective activity, were synthesized in a selective manner.

Chromium(0)-promoted multicomponent cycloaddition of tethered diynes with cyclic trienes: application to the total synthesis of 9-epi-pentalenic acid.

An efficient protecting group controlled regioselective chromium(0)-mediated three-component higher order cycloaddition of tethered diynes with cyclic trienes that generates five rings and six stereogenic centers in one step is described. Following a sequence of reactions featuring a chemoselective Baeyer-Villiger rearrangement and a regioselective cyclopropane hydrogenolysis, the total synthesis of 9-epi-pentalenic acid was achieved.

Nickel-Catalyzed Cyclizations of Enoate Equivalents: Application to the Synthesis of Angular Triquinanes

Unsaturated acyloxazolidinones and α‘-silyloxy enones were found to be effective substrates in nickel-catalyzed organozinc-promoted cyclizations. Both groups served as convenient enoate equivalents, whereas methyl enoates themselves were inefficient substrates. A five-step procedure for the conversion of dimethylcyclopentenone into a highly functionalized angular triquinane was developed utilizing this observation. The key step of the procedure involves a nickel-catalyzed reductive cyclization/Dieckmann condensation sequence involving a cyclic enone tethered to an unsaturated acyloxazolidinone or α‘-silyloxy enone. The method was applied in a formal synthesis of pentalenene, pentalenic acid, and deoxypentalenic acid.

The Pauson-Khand reaction in triquinane synthesis: approaches to pentalenene, pentalenic acid, and silphinene

Substituted pentynylcyclopentene precursors for the synthesis of pentalenene, pentalenic acid, and silphinene by intramolecular Pauson-Khand cycloaddition reaction have been prepared from 2-methylcyclopentanone via 5-methylcyclopentenyllithium. Conjugate addition of the latter to BHT methacrylate followed by methylation were the key steps in enyne syntyhesis. Reaction of 4,4-dimethyl-5(5-methylcyclopentenyl)-1-pentyne with Co 2 (CO) 8 produces two diastereomeric triquinane enones in an overall yield of 51%, with the exo-9-methyl isomer predominating by ratio of 8:1. This material was converted into pentalenene in two steps. Pauson-Khand reaction of the TBDMS ether of 4,4-dimethyl-5-(5-methylcyclopentenyl)-1-pentyn-3-ol proceeds in 33%

Zipper-mode cascade carbometallation for construction of polycyclic structures

Abstract

Highly stereo- and regiocontrolled cyclopentannulation via allylphosphonate conjugate addition and hydroboration-oxidation-elimination. Synthesis of pentalenic acid with virtually complete stereo- and regiocontrol

Highly stereo- and regiocontrolled cyclopentannulation via allylphosphonate conjugate addition and hydroboration-oxidation-elimination. Synthesis of pentalenic acid with virtually complete stereo- and regiocontrol

Application of the Pauson–Khand reaction to the synthesis of pentalenic acid

A substituted penthynylcyclopentene precursor for the synthesis of pentalenic acid by intramolecular Pauson–Khand cycloaddition reaction has been prepared in high yield. Reaction with Co 2(CO) 8 produces triquinane econes in an overall yield of 33%. Three of the four possible stereoisomeric products are formed, with two of them, making up ca. 80% of the product mixture, possessing the necessary exo-methyl stereochemistry at C-9 for further elaboration into pentalenic acid. A formal synthesis of the latter was completed by reduction of one of the enone isomers into a ketone which had previously been carried on to the natural product.

Total synthesis of (±)-pentalenene, (±)-pentalenic acid, and (±)deoxypentalenic acid through an intramolecular double Michael reaction

The angular triquinane sesquiterpenes, (±)-pentalenene (1), (±)-pentalenic acid (2), and (±)-deoxypentalenic acid (4), were synthesized via the intramolecular double Michael reaction as the key step. Heating the bis-enone (10), prepared from 4,4-dimethylcyclopent-2-enone (11) in six steps, with chlorotrimethylsilane, triethylamine, and zinc chloride gave the tricyclo[7.3.0.0]dodecanedione (9), which was converted into the above triquinanes after ring contraction.

Total synthesis of (±)-pentalenic acid via intramolecular double Michael reaction

An efficient total synthesis of (±)-pentalenic acid (2) has been achieved via intramolecular double Michael reaction as the key step.

System oriented design of triquinanes: stereocontrolled synthesis of pentalenic acid and pentalenene

Pentalenic acid, 5, and pentalenene, 4, and their C-9 epimers 5a and 4a, respectively, were synthesized using [4+1] and [2+3] cyclopentene annulation methodology. The key steps involved internal cyc1opropanation of dienes 23 or cyc1opropanation of enone 25 followed by the thermolytic rearrangements of cyclopropanes 24, 39, 42, 45, and 48 to furnish triquinanes 26 and 40. An investigation of electronic effects affecting the diradical cleavage of viny1cyclopropanes was performed. The triquinanes 26 or 40 were transformed to the title compounds by reductive operations at C-9. The equilibration of esters 60 at C-9 was briefly addressed in the context of molecular mechanics predictions regarding the thermodynamic stabilities of conformations at C-9 in the natural vs. the epi series. The stereoselectivities in approaches to natural hydrocarbons and their C-9 epimers were evaluated as better than 9:1 in each series.

Intramolecular photocycloadditions-cyclobutane fragmentation: total synthesis of (.+-.)-pentalenene, (.+-.)-pentalenic acid, and (.+-.)-deoxypentalenic acid

Pentalenene, pentalenic acid, and deoxypentalenic acid, important metabolites in the biosynthesis of the pentalenolactones, have been synthesized from methyl isobutyrate through a common intermediate. The initial key step involves a novel conjugate addition-cycloacylation sequence on an acetylenic diester. The 1,6-diene which results is converted in two steps to a 1,6-diene diester which undergoes a highly stereoselective photocycloaddition to set three of the necessary stereocenters. Reductive cleavage of one cyclobutane bond produces a functionalized spirobicyclo(4.4)nonanone which is converted in three steps to dione 10, the pivotal intermediate. Differential functionalization of this system provides efficient, stereocontrolled routes to pentalenene, pentalenic acid, and deoxypentalenic acid, all in racemic form.

Intramolecular photocycloaddition-cyclobutane fragmentation: a highly stereoselective total synthesis of (+-)-pentalenic acid

Intramolecular photocycloaddition-cyclobutane fragmentation: a highly stereoselective total synthesis of (+-)-pentalenic acid