Systematic Route to Construct the 5-5-6 Tricyclic Core of Furanobutenolide-Derived Cembranoids and Norcembranoids.

Herein, we present a highly efficient method for constructing the intricate 5-5-6 fused ring system commonly found in the polycyclic furanobutenolide-derived cembranoid and norcembranoid natural product family with remarkable diastereoselectivity, utilizing an intramolecular Diels-Alder reaction as the cornerstone. Notably, employing a propargyl ether tether as the dienophile yields significant enhancements in the transformation process compared to its propargyl ester counterpart, as demonstrated in our previous total synthesis of havellockate. This advancement holds promising implications for future investigations, offering a streamlined pathway for rapidly assembling the tricyclic core characteristic of this diverse family of natural products.

Novel Insecticidal Butenolide-Containing Methylxanthine Derivatives: Synthesis, Crystal Structure, Biological Activity Evaluation, DFT Calculation and Molecular Docking.

The design of novel agrochemicals starting from bioactive natural products is one of the most effective ways in the discovery and development of new pesticidal agents. In this paper, a series of novel butenolide-containing methylxanthine derivatives (Ia-Ir) were designed based on natural methylxanthine caffeine and stemofoline, and the derivatized insecticide flupyradifurone of the latter. The structures of the synthesized compounds were confirmed via 1H-NMR, 13C NMR, HRMS and X-ray single crystal diffraction analyses. The biological activities of the compounds were evaluated against a variety of agricultural pests including oriental armyworm, bean aphid, diamondback moth, fall armyworm, cotton bollworm, and corn borer; the results indicated that some of them have favorable insecticidal potentials, particularly toward diamondback moth. Among others, Ic and Iq against diamondback moth possessed LC50 values of 6.187 mg ⋅ L-1 and 3.269 mg ⋅ L-1, respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC50=15.743 mg ⋅ L-1). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compound (Ic). Ic and Iq derived from the integration of caffeine (natural methylxanthine) and butenolide motifs can serve as novel leading insecticidal compounds for further optimization.

Proposal for structure revision of pinofuranoxin A through total syntheses of stereoisomers.

The relative configuration of the epoxide functionality in pinofuranoxin A (1), α-alkylidene-ß-hydroxy-γ-methyl-γ-butyrolactone with trans-epoxy side chain isolated by Evidente et al. in 2021, was revised by DFT-based spectral reinvestigations and stereo-controlled synthesis. The present investigation demonstrates the difficulty of the configurational elucidation of the stereogenic centers on the conformationally flexible acyclic side-chains. Sharpless's enantioselective epoxidations and dihydroxylations were quite effective in the reinvestigations of the configurations. As our syntheses made all diastereomers available, these would be quite effective in the next structure-biological activity relationship studies.

Prebiotically plausible chemoselective pantetheine synthesis in water.

Coenzyme A (CoA) is essential to all life on Earth, and its functional subunit, pantetheine, is important in many origin-of-life scenarios, but how pantetheine emerged on the early Earth remains a mystery. Earlier attempts to selectively synthesize pantetheine failed, leading to suggestions that "simpler" thiols must have preceded pantetheine at the origin of life. In this work, we report high-yielding and selective prebiotic syntheses of pantetheine in water. Chemoselective multicomponent aldol, iminolactone, and aminonitrile reactions delivered spontaneous differentiation of pantoic acid and proteinogenic amino acid syntheses, as well as the dihydroxyl, gem-dimethyl, and ß-alanine-amide moieties of pantetheine in dilute water. Our results are consistent with a role for canonical pantetheine at the outset of life on Earth.

Cadiolide analogues and their precursors as new inhibitors of bacterial quorum sensing and biofilm formation.

Bacterial quorum sensing (QS) and biofilm formation are promising targets for developing new therapies to treat chronic infections. Herein, we report the stereoselective synthesis of 18 new analogs of natural cadiolides. Among the new compounds, substances 8b, 8f, 8i, 9a, 9b and 9e completely inhibited the biofilm formation of Escherichia coli RP347 in vitro. In addition, compound 8b interfered acyl-homoserine lactone (AHL) mediated QS, while 9e interrupted the QS via autoinducer-2 (AI-2). Biological assays also revealed that synthetic intermediates alkynones are potent inhibitors of AI-2 and AHL-mediated QS. These results indicate that cadiolides and alkynones are good candidates for further structural modification for a new generation of more potent antimicrobial agents.

Ligand-controlled divergent dehydrogenative reactions of carboxylic acids via C-H activation.

Dehydrogenative transformations of alkyl chains to alkenes through methylene carbon-hydrogen (C­H) activation remain a substantial challenge. We report two classes of pyridine-pyridone ligands that enable divergent dehydrogenation reactions through palladium-catalyzed ß-methylene C­H activation of carboxylic acids, leading to the direct syntheses of α,ß-unsaturated carboxylic acids or γ-alkylidene butenolides. The directed nature of this pair of reactions allows chemoselective dehydrogenation of carboxylic acids in the presence of other enolizable functionalities such as ketones, providing chemoselectivity that is not possible by means of existing carbonyl desaturation protocols. Product inhibition is overcome through ligand-promoted preferential activation of C(sp3)­H bonds rather than C(sp2)­H bonds or a sequence of dehydrogenation and vinyl C­H alkynylation. The dehydrogenation reaction is compatible with molecular oxygen as the terminal oxidant.

Construction of Enantioenriched γ,γ-Disubstituted Butenolides Enabled by Chiral Amine and Lewis Acid Cascade Cocatalysis.

Herein we report a cascade cocatalysis strategy for the facile construction of chiral γ,γ-disubstituted butenolides. The synthetic manifold employs simple alkynoic acids instead of the preformed silyloxy furans or 5-substituted furan-2(3H)-ones. In situ formed 5-substituted furan-2(3H)-ones by AgNO3 or Ph3PAuCl/AgOTf catalyzed cyclization of alkynoic acids can smoothly engage in the subsequent chiral diphenylprolinol TMS-ether catalyzed Michael and Michael-aldol reactions. The cascade process serves as a general approach to chiral quaternary γ,γ-disubstituted butenolides.

Concise Synthesis of Both Enantiomers of Pilocarpine.

Furan-2-carboxylic acid was used as a starting material for the synthesis of dehydro-homopilopic acid. Esterification, hydrogenation and enzymatic hydrolysis followed by the reduction of Weinreb amides and a single-step attachment of a 1-methyl-imidazole residue allowed for the concise synthesis of both enantiomers of pilocarpine.

Chiral Bifunctional Phosphine Ligand-Enabled Cooperative Cu Catalysis: Formation of Chiral α,ß-Butenolides via Highly Enantioselective γ-Protonation.

α,ß-Butenolides with ≥96% enantiomeric excess are synthesized from ß,γ-butenolides via a novel Cu(I)-ligand cooperative catalysis. The reaction is enabled by a chiral biphenyl-2-ylphosphine ligand featuring a remote tertiary amino group. Density functional theory studies support the cooperation between the metal center and the ligand basic amino group during the initial soft deprotonation and the key asymmetric γ-protonation. Remarkably, other coinage metals, that is, Ag and Au, can readily assume the same role as Cu in this asymmetric isomerization chemistry.

Optimization of (-)-cubebin biotransformation to (-)-hinokinin by the marine fungus Absidia coerulea 3A9.

The genus Absidia is widely used in the biotransformation of different classes of natural products. This study evaluates the ability of the Absidia coerulea 3A9 marine derived strain isolated from the ascidian Distaplia stilyfera to perform biotransformations by conducting assays with (-)-cubebin, as substrate. The experiment was optimized using the experimental design proposed by Plackett-Burman for seven factors and eight experiments, to establish the biotransformation conditions that would allow maximum production of biotransformed dibenzylbutyrolactone (-)-hinokinin. An analytical method based on Reverse-Phase-High Performance Liquid Chromatography (RP-HPLC) was developed to quantify the fungal biotransformation product. The factor that influenced the (-)-hinokinin peak area the most positively was the percentage of seawater (%seawater) given that its %relative standard deviation (%RSD) showed a 32.92% deviation from the real value.

Utility of novel 2-furanones in synthesis of other heterocyclic compounds having anti-inflammatory activity with dual COX2/LOX inhibition.

Inflammation is associated with the development of several diseases comprising cancer and cardiovascular disease. Agents that suppress cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, besides chemokines have been suggested to minimise inflammation. Here, a variety of novel heterocyclic and non-heterocyclic compounds were prepared from novel three furanone derivatives. The structures of all synthesised compounds were confirmed by elemental and spectral analysis including mass, IR, and 1H-NMR spectroscopy. Anti-inflammatory activities of these synthesised compounds were examined in vitro against COX enzymes, 15-LOX, and tumour necrosis factor-α (TNF-α), using inhibition screening assays. The majority of these derivatives showed significant to high activities, with three pyridazinone derivatives (5b, 8b, and 8c) being the most promising anti-inflammatory agents with dual COX-2/15-LOX inhibition activities along with high TNF-α inhibition activity.

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones.

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.

Synthesis of novel phytol-derived γ-butyrolactones and evaluation of their biological activity.

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported. Products were obtained in good yields (19-96%) and their structures were fully characterized by spectroscopic data (NMR, HRMS). Four synthesized δ-halo-γ-lactones (4-7) are new and have not been previously described in the literature. In the choice test phytol (1) appeared deterrent to M. persicae, whereas modifications of its structure did not cause the avoidance of the treated leaves by the aphids. In contrast, aphids were attracted to the leaves treated with the new trans-δ-chloro-γ-lactone (6). Electrical Penetration Graph (EPG) technique applied to explore the aphid probing and feeding activity revealed that neither phytol nor lactone 6 affected aphid probing and the consumption of phloem sap, which means that both phytol and the lactone 6 might have acted as postingestive modifiers of aphid behavior. The results of in vitro antitumor assays showed that obtained phytol derivatives exhibit cytotoxic activity against studied cancer cell lines (leukemia, lung and colon carcinoma and its doxorubicin resistant subline). Halolactones 4-6 were identified as the compounds, which arrest cell cycle of leukemia cells mainly in G2/M and S phases.

Synthesis of nature product kinsenoside analogues with anti-inflammatory activity.

Kinsenoside is the major bioactive component from herbal medicine with a broad range of pharmacological functions. Goodyeroside A, an epimer of kinsenoside, remains less explored. In this report we chemically synthesized kinsenoside, goodyeroside A and their analogues with glycan variation, chirality inversion at chiral center(s), and bioisosteric replacement of lactone with lactam. Among these compounds, goodyeroside A and its mannosyl counterpart demonstrated superior anti-inflammatory efficacy. Furthermore, goodyeroside A was found to suppresses inflammatory through inhibiting NF-κB signal pathway, effectively. Structure-activity relationship is also explored for further development of more promising kinsenoside analogues as drug candidates.

(2R)- and (2S)- 2-hydroxy- hexanoyl and octanoyl-l-homoserine lactones: New highly potent Quorum Sensing modulators with opposite activities.

The synthesis and the QS modulation activity of diastereoisomerically pure 2-hydroxy-N-acyl-l-homoserine lactones (2-OH-AHLs) are unveiled. (2R)- and (2S)- 2-hydroxy-N-hexanoyl-l-homoserine lactone and 2-hydroxy-N-octanoyl-l-homoserine lactone have been identified as very potent QS agonists and antagonists on the Vibrio fischeri-quorum sensing system with opposite activities depending on the configuration of the carbon atom with the hydroxyl group. Flexible molecular docking showed that the (2R)-OH configuration in the antagonist isomer induces new hydrogen bonds with Tyr70 and Asp79, two importantly conserved residues in the LuxR protein family, while the (2S)-OH agonist configuration exhibits a binding mode comparable to the natural ligand 3-oxo-hexanoyl-l-homoserine lactone (OHHL). For the analogs with long alkyl chain 3a and 3b and aromatic analogs, all are antagonists with no effect of the configuration at C-2.

Next generation quorum sensing inhibitors: Accounts on structure activity relationship studies and biological activities.

Bacterial resistance is a growing threat which represents major scourge throughout the world. The suitable way to control the present critical situation of antimicrobial resistance would be to develop entirely novel strategies to fight antibiotic resistant pathogens such as quorum sensing (QS) inhibitors or its combination with antibiotics. Anti QS agents can eliminate the QS signals and put the barrier in bio-film formation, consequently, bacterial virulence will be reduced without causing drug-resistance to the pathogens. Among the various anti QS agents identified, especially those of natural origin, furanones or acylatedhomoserine lactones (AHLs) are most popular. Semi-synthetic and synthetic inhibitors have shown greatest potential and have inspired chemists to design synthetically modified QS inhibitors with lactone moiety. This review focuses on anti QS agents (bio-film inhibitors) of both natural and synthetic origins. Further, the synthesis, structure activity relationship and anti QS activity covering literature from 2015 till March 2020 has been discussed.

New antibacterial cadiolide analogues active against antibiotic-resistant strains.

The synthesis of new cadiolide analogues was carried out using a one-pot multi component synthesis. The antibacterial activity of these molecules was evaluated on standard and antibiotic resistant bacterial strains chosen for their involvement in human health or in food-born poisoning. Four molecules have shown good activities with MICs of 2 µg/mL-1. The introduction of an indole group or the conversion of the lactone into lactam have highlighted two new families of molecules with promising antibacterial activity. In addition, most of these active molecules are devoid of cytotoxic activity against keratinocyte cells.

ß,γ-Diaryl α-methylene-γ-butyrolactones as potent antibacterials against methicillin-resistant Staphylococcus aureus.

A selected series of racemic α-methylene-γ-butyrolactones (AMGBL) synthesized via allylboration or allylindation reactions were screened against methicillin-resistant Staphylococcus aureus (MRSA) USA300. Unlike natural AMGBLs, such as parthenolide, synthetic analogs bearing aryl moieties at the ß- and γ-positions are potent against MRSA. The most potent molecules were comparable to vancomycin and linezolid, the drugs of the last resort for MRSA infections, in their effectiveness with minimum inhibitory concentrations (MICs) ranging from 3.0 to 5.2 µM. These lactones also exhibited potent antibacterial activity against other clinically important multidrug-resistant Gram-positive bacteria (except enterococci), while also showing high tolerability to mammalian cells. Several of these molecules surpassed vancomycin in their rapid killing of the high MRSA inoculum (2 h vs 12 h) in a standard time-kill kinetics assay, with compounds 1l and 1m significantly reducing the intracellular burden of MRSA by about 98-99%, at low concentrations. Additionally, the compounds surpassed vancomycin in inhibiting staphylococcal protease production, indicating that synthetic methylene lactones warrant further investigations as promising anti-MRSA candidates.

Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors.

The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD50 values of 29.3 ± 3.0 mM and 123.5 ± 13.0 mM, respectively. Both compounds were tested against recombinant human α1 glycine receptors in HEK293 cells using whole-cell recording techniques. Both, SN and DSN were shown for the first time to be inhibitors of recombinant glycine receptors, with KIvalues of 2.1 ± 0.3 µM for SN, and 109 ± 9 µM for DSN. Receptor inhibition was also studied in vivo in a mouse model of strychnine toxicity. Surprisingly, in mouse experiments strychnine inhibition was not augmented by either terpenoid. While DSN had no significant effect on strychnine toxicity, SN even delayed strychnine effects. This could be accounted for by assuming that strychnine and sarcophine derivatives compete for the same binding site on the receptor, so the less toxic sarcophine can prevent strychnine from binding. The combination of modulatory activity and low level of toxicity makes sarcophines attractive structures for novel glycinergic drugs.

Synthesis and evaluation of heterocycle structures as potential inhibitors of Mycobacterium tuberculosis UGM.

In this study, we screen three heterocyclic structures as potential inhibitors of UDP-galactopyranose mutase (UGM), an enzyme involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis. In order to understand the binding mode, docking simulations are performed on the best inhibitors. Their activity on Mycobacterium tuberculosis is also evaluated. This study made it possible to highlight an "oxazepino-indole" structure as a new inhibitor of UGM and of M. tuberculosis growth in vitro.