Acid Lactone Research Articles

A new lindenane-type sesquiterpenoid lactone from Chloranthus japonicus

Chromatographic fractionation of the EtOH extracts of the Traditional Chinese Medicine (TCM) Chloranthus japonicus, has led to the isolation of a new lindenane-type sesquiterpenoid lactone derivative (1). Rosmarylchloranthalactone E (1), which consists of lindenane sesquiterpenoid lactone and rosmarinic acid moieties linked via an ester bridge, was structurally elucidated by 1D and 2D NMR and HRMS data. Compound 1 was a potent phosphodiesterase-4 (PDE4) inhibitor with an IC50 value of 0.96 ± 0.04 μM.

Copper catalyzed one-pot difluoroalkylation and lactonization of unsaturated carboxylic acids

A new cost-effective method for one-pot bifunctionalization of unsaturated carboxylic acids to afford difluoroalkylated γ-lactones has been reported using a Cu(i) catalyst.

Chemoenzymatic macrocycle synthesis using resorcylic acid lactone thioesterase domains.

A key missing tool in the chemist's toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Macrocyclic natural product biosynthesis offers an obvious starting point for biocatalyst discovery via the native macrocycle forming biosynthetic mechanism. Herein we demonstrate that the thioesterase domains (TEs) responsible for macrocyclization of resorcylic acid lactones are promising catalysts for the chemoenzymatic synthesis of 12- to 18-member ring macrolactones and macrolactams. The TE domains responsible for zearalenone and radicicol biosynthesis successfully generate resorcylate-like 12- to 18-member macrolactones and a 14-member macrolactam. In addition these enzymes can also macrolactonize a non-resorcylate containing depsipeptide, suggesting they are versatile biocatalysts. Simple saturated omega-hydroxy acyl chains are not macrocyclized, nor are the alpha-beta unsaturated derivatives, clearly outlining the scope of the substrate tolerance. These data dramatically expand our understanding of substrate tolerance of these enzymes and are consistent with our understanding of the role of TEs in iterative polyketide biosynthesis. In addition this work shows these TEs to be the most substrate tolerant polyketide macrocyclizing enzymes known, accessing resorcylate lactone and lactams as well as cyclicdepsipeptides, which are highly biologically relevant frameworks.

Bio-based triacetic acid lactone in the synthesis of azaheterocyclesviaa ring-opening transformation

In the present article a new way of converting biobased triacetic acid lactone (TAL) into azaheterocyclic compounds, such as 4-pyridones, pyrazoles, isoxazolines and isoxazoles, has been found through reactive and multifunctional polycarbonyl intermediates.

Study of Antioxidant and Anti-Inflammatory Crude Methanol Extract and Fractions of Acacia seyal Gum

Acacia seyal gum (ASG) is a dried exudate from tropical plants in the family Leguminosae. It has been used in the medication of eczema, inflammation, renal failure, and hypertension in folk medicine. This study presents methanol crude extracts (MCE) and different fractions of ASG in the form of raw (ASG) and commercial type Prebio-T, (PTC) using different solvents. Evaluations were performed to observe the biological activities of the extracts and fractions with certain bioassays procedure of anti-inflammatory, total phenolic content (TPC) and radical scavenging activity (DPPH). The only MCE was assessed against inflammatory reaction using carrageenan paw oedema (in-vivo). However, the antioxidant activities of MCE and its fractions were evaluated. As a result, the highest amount of TPC was observed in the Prebio-T, with an average of 694.68 ± 3.60 mgTE/100 g DW, compared to only 155.78 ± 2.58 mg TE/100 g DW for ASG Crude Extract. The highest DPPH value was seen in methanol fraction (MF) was 235.34 ± 1.57 mg TE/100 g DW for Prebio-T, compared to ASG without any significant differences (p ≤ 0.05). Both MCE of ASG and Prebio-T at 150 mg/kg dosage developed a mean and maximum percentage inhibition of 23.63% and 23.54% respectively, during the 24h observation of the acute inflammatory test. The chemical composition of the 57 phenolic compounds in methanol crude extract (MCE), and its active fractions were detected using GC-MS/MS. The major constituents in the ASG and Prebio-T MCE were iso vitamin C (42.37%), crypton (5.86%), hydroquinone (4.86%), triacetic acid lactone (2.67%), 2,4-Di-tert-butyl phenol (2.67%), cyanidin cation (2.05%), apigenin 7-glucoside (1.9%), benzoic acid (1.83%), (+)-α-tocopherol (1.58%), methyl catechol (1.42%), and 2,6-dimethylol-pcresol (2.16%). The PBT methanolic crude extract (MCE) was found to be the most potent inhibitor of oedema formation by inducing a maximum inhibitory effect of 23.54% at the 300 mg/kg dose, during 24h post-carrageenan injection. Both PBT and ASG methanolic crude extracts showed good anti-inflammatory activities at the same dose (300 mg/kg). The results of these studies support the potential use of ASG for treating inflammation.

Resorcylic acid lactones (RALs) and their structural congeners: recent advances in their biosynthesis, chemical synthesis and biology

Resorcylic acid lactones (RALs) are naturally occurring 14-membered macrolactones that constitute a class of polyketides derived from fungal metabolites and that possess significant and promising biological activity.

Total Synthesis and Cytotoxic Activity of 5′‐Hydroxyzearalenone and 5′β‐Hydroxyzearalenone

An efficient and convergent synthesis of 5′‐hydroxyzearalenone and 5′β‐hydroxyzearalenone, 14‐membered β‐resorcylic acid lactone (RAL) natural products, has been achieved in a longest linear sequence of 19 steps, and a total of 29 steps, starting from commercially available 5‐hexen‐1‐ol and methyl 2‐(3,5‐dimethoxyphenyl)acetate. The key features of our synthesis include a Jacobsen hydrolytic kinetic resolution, a Mitsunobu esterification and (an E)‐selective ring‐closing metathesis (RCM). Our synthesis also highlights the utility of the acetal protecting group for the resorcylate moiety, and its compatibility with RCM reactions for the synthesis of 14‐membered RALs. The cytotoxic activity of both synthetic compounds was evaluated against seven human cancer cell lines. 5′‐Hydroxyzearalenone shows more potent cytotoxic activity against most of the cancer cell lines tested than its epimer, 5′β‐hydroxyzearalenone. Both compounds show significant cytotoxic activity against the C33A cervical cancer cell line, with IC50 values of 21.33 ± 6.43 µm and 16.00 ± 12.17 µm, respectively.

A New Dihydrochromone Dimer and Other Secondary Metabolites from Cultures of the Marine Sponge-Associated Fungi Neosartorya fennelliae KUFA 0811 and Neosartorya tsunodae KUFC 9213.

A previously unreported dihydrochromone dimer, paecilin E (1), was isolated, together with eleven known compounds: β-sitostenone, ergosta-4,6,8 (14), 22-tetraen-3-one, cyathisterone, byssochlamic acid, dehydromevalonic acid lactone, chevalone B, aszonalenin, dankasterone A (2), helvolic acid, secalonic acid A and fellutanine A, from the culture filtrate extract of the marine sponge-associated fungus Neosartorya fennelliae KUFA 0811. Nine previously reported metabolites, including a chromanol derivative (3), (3β, 5α, 22E), 3,5-dihydroxyergosta-7,22-dien-6-one (4), byssochlamic acid, hopan-3β,22-diol, chevalone C, sartorypyrone B, helvolic acid, lumichrome and the alkaloid harmane were isolated from the culture of the marine-sponge associated fungus Neosartorya tsunodae KUFC 9213. Paecilin E (1), dankasterone A (2), a chromanol derivative (3), (3β, 5α, 22E)-3,5-dihydroxyergosta-7,22-dien-6-one (4), hopan-3β,22-diol (5), lumichrome (6), and harmane (7) were tested for their antibacterial activity against Gram-positive and Gram-negative reference and multidrug-resistant strains isolated from the environment. While paecilin E (1) was active against S. aureus ATCC 29213 and E. faecalis ATCC 29212, dankastetrone A (2) was only effective against E. faecalis ATCC 29212 and the multidrug-resistant VRE E. faecalis A5/102. Both compounds neither inhibit biofilm mass production in any of the strains at the concentrations tested nor exhibit synergistic association with antibiotics.

Urinary Metabolomic Profiling to Identify Potential Biomarkers for the Diagnosis of Behcet's Disease by Gas Chromatography/Time-of-Flight-Mass Spectrometry.

Diagnosing Behcet’s disease (BD) is challenging because of the lack of a diagnostic biomarker. The purposes of this study were to investigate distinctive metabolic changes in urine samples of BD patients and to identify urinary metabolic biomarkers for diagnosis of BD using gas chromatography/time-of-flight–mass spectrometry (GC/TOF−MS). Metabolomic profiling of urine samples from 44 BD patients and 41 healthy controls (HC) were assessed using GC/TOF−MS, in conjunction with multivariate statistical analysis. A total of 110 urinary metabolites were identified. The urine metabolite profiles obtained from GC/TOF−MS analysis could distinguish BD patients from the HC group in the discovery set. The parameter values of the orthogonal partial least squared-discrimination analysis (OPLS-DA) model were R2X of 0.231, R2Y of 0.804, and Q2 of 0.598. A biomarker panel composed of guanine, pyrrole-2-carboxylate, 3-hydroxypyridine, mannose, l-citrulline, galactonate, isothreonate, sedoheptuloses, hypoxanthine, and gluconic acid lactone were selected and adequately validated as putative biomarkers of BD (sensitivity 96.7%, specificity 93.3%, area under the curve 0.974). OPLS-DA showed clear discrimination of BD and HC groups by a biomarker panel of ten metabolites in the independent set (accuracy 88%). We demonstrated characteristic urinary metabolic profiles and potential urinary metabolite biomarkers that have clinical value in the diagnosis of BD using GC/TOF−MS.

Biosensor-aided high-throughput screening of hyper-producing cells for malonyl-CoA-derived products

BackgroundMalonyl-coenzyme A (CoA) is an important biosynthetic precursor in vivo. Although Escherichia coli is a useful organism for biosynthetic applications, its malonyl-CoA level is too low.ResultsTo identify strains with the best potential for enhanced malonyl-CoA production, we developed a whole-cell biosensor for rapidly reporting intracellular malonyl-CoA concentrations. The biosensor was successfully applied as a high-throughput screening tool for identifying targets at a genome-wide scale that could be critical for improving the malonyl-CoA biosynthesis in vivo. The mutant strains selected synthesized significantly higher titers of the type III polyketide triacetic acid lactone (TAL), phloroglucinol, and free fatty acids compared to the wild-type strain, using malonyl-CoA as a precursor.ConclusionThese results validated this novel whole-cell biosensor as a rapid and sensitive malonyl-CoA high-throughput screening tool. Further analysis of the mutant strains showed that the iron ion concentration is closely related to the intracellular malonyl-CoA biosynthesis.

Detection of new phenylpropanoids from Dendrobium chrysanthum

Herba Dendrobii has been documented in the Compendium of Materia Medica, with special efficacy in nourishing Yin and treating diabetes. However, the chemical profile of Dendrobium chrysanthum Lindl. has not been reported yet. The compositions were analysed with UPLC/Q-TOF-MS/MS. 53 compounds were tentatively characterised, and 14 compounds might be new compounds. Some novel lactones of poly-phenylpropanoids were firstly detected, and di-p-hydroxyphenylpropionic acidic p-coumaric acid lactone, a new compound of the first example, was obtained and identified. UPLC/Q-TOF-MS/MS was a feasible and efficient method to discover the unique compounds in complex matrices of D. chrysanthum.

Mechanistic and Synthetic Investigations on the Dual Selenium-π-Acid/Photoredox Catalysis in the Context of the Aerobic Dehydrogenative Lactonization of Alkenoic Acids

The aerobic dehydrogenative lactonization of alkenoic acids facilitated by a cooperative nonmetallic catalyst pair is reported. The title procedure relies on the adjusted interplay of a photoredox and a selenium-π-acid catalyst, which allows for the regiocontrolled construction of five- and six-membered lactone rings in yields of up to 96%. Notable features of this method are pronounced efficiency and practicality, good functional group tolerance, and high sustainability, since ambient air and visible light are adequate for the clean conversion of alkenoic acids into their respective lactones. The title method has been used as a case study to elucidate the general mechanistic aspects of the dual selenium-π-acid/photoredox catalysis. On the basis of NMR spectroscopic, mass spectrometric, and computational investigations, a more detailed picture of the catalytic cycle is drawn and the potential role of trimeric selenonium cations as catalytically relevant species is discussed.

Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives

Ten antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95 μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50 > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22 μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2 μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectively.

Study of the structure, the electronic and spectral properties of D-glucaro-dilactones

The double lactonization of D-glucaric acid can result in two isomeric molecules which are: the D-glucaro-1,4:6,3-dilactone and the D-glucaro-1,5:6,3-dilactone. In the present article we try to understand the differences between these molecules. To this end, all the conformations have been modeled and optimized in order to find the most stable structures. Energies, frontier orbitals (HOMO and LUMO) as well as other electronic and spectral properties have been calculated in vacuum, acidic and aqueous media using the polarizable continuum model (PCM). The calculations were investigated by performing semi-empirical PM6 and density functional theory (DFT) at the B3LYP level of theory. The obtained results do not motivate a possible observation of the two dilactones simultaneously in the same medium, which explains the absence of this coexistence in the scientific works carried out to date.

Photoinduced Regioselective Lactonization of ortho-Iodobenzoic Acids with Alkenes: Synthesis of 3,4-Dihydroisocoumarin Derivatives

A photoinduced strategy for the synthesis of a variety of 3,4-dihydroisocoumarins has been realized. The reactions proceeded from ortho-iodobenzoic acids and alkenes through a photodehalogenative lactonization with NaHCO3 as the only additive in dimethyl sulfoxide (DMSO) to provide the desired products in moderate to good yields. This method offers a simple, mild, and environmentally friendly route to 3,4-dihydroisocoumarin derivatives.

Antifungal and Cytotoxic β-Resorcylic Acid Lactones from a Paecilomyces Species.

Eight new β-resorcylic acid lactones (RALs), including the hypothemycin-type compounds paecilomycins N-P (1-3) and the radicicol-type metabolites dechloropochonin I (4), monocillins VI (5) and VII (6), 4'-hydroxymonocillin IV (7), and 4'-methoxymonocillin IV (8), along with nine known RALs (9-17), were isolated from the cultures of Paecilomyces sp. SC0924. Compounds 1 and 2 feature a novel 6/11/5 ring system, and 3 is the first 5'-keto RAL. The structures of 1-8 were elucidated on the basis of extensive spectroscopic analysis, X-ray diffraction analysis, and theoretical calculations of ECD spectra. Compounds 3, 5, and 6 exhibit cytotoxicity against MCF-7, A549, and HeLa cells, and compounds 5 and 7 display antifungal activity against Peronophythora litchii.

Total synthesis of greensporone C

The first total synthesis of greensporone C, a cytotoxic 14-membered resorcylic acid lactone, has been accomplished via a longest linear sequence of 16 steps in 3.3% overall yield. The key features of the synthesis include Mitsunobu esterification and ring-closing metathesis to construct the macrocycle and establish the (E)-olefin geometry, respectively. Our synthesis also confirmed the absolute stereochemistry of the natural product.

(HMe2SiCH2)2: A Useful Reagent for B(C6F5)3-Catalyzed Reduction–Lactonization of Keto Acids: Concise Syntheses of (–)-cis-Whisky and (–)-cis-Cognac Lactones

(HMe2SiCH2)2 has been utilized as a useful reagent for B(C6F5)3-catalyzed reduction–lactonization of keto acids to synthesize γ- and δ-lactones. The process led concisely to (–)-cis-whisky and (–)-cis-cognac lactones in respective overall yields of 32% and 36%.

Capillary zone electrophorsis for the analysis of naturally occurring 2-hydroxycitric acids and their lactones.

A simple capillary zone electrophoresis method with direct ultraviolet detection has been developed for the analysis of naturally occurring diastereomeric 2-hydroxycitric acid lactones. Using 50mM sodium phosphate buffer of pH 7, a baseline resolution Rs > 3.0 was observed for all organic acids selected for the present study. This method was employed for the quantitative determination of title acids present in the plant sources namely Garcinia cambogia fruit rinds and Hibiscus sabdariffa calyx. Conversion of 2-hydroxycitric acids to their lactones on heating the above plant sources is deliberated. The Hydrolysis of hydroxycitric acid lactones in aqueous solution is reported for the first time.

Antiproliferative activity against leukemia cells of sesquiterpene lactones from the Turkish endemic plant Centaurea drabifolia subsp. detonsa

The apolar organic extract obtained from aerial parts of Centaurea drabifolia Sibth. & Sm. subsp. detonsa (Bornm.) Wagenitz, growing wild in Turkey, was investigated for the first time for its secondary metabolite composition. Seven sesquiterpene lactones belonging to the guaiane class (1–7), including the new compound 4, along with a fatty acid lactone derivative (8), were isolated. The structures of these compounds were established by spectroscopic analysis, including 2D NMR spectroscopic techniques, with the stereostructure of the new guaiane 4 determined with the help of MTPA derivatization. Cytotoxic activities of compounds 1–7 were evaluated against two cancer cell lines, namely acute lymphoblastic leukemia (CCRF-CEM) and its multidrug-resistant subline CEM/ADR5000. Results showed that aguerin B (1) and cynaropicrin (2) showed a potent activity on both cell lines revealing interesting details about the structure-activity relationships in the class of acylated guaiane sesquiterpenes.