Synthesis of obovatol and related neolignan analogues as α-glucosidase and α-amylase inhibitors.

Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which can be counteracted by the inhibition of α-glucosidase (α-Glu) and α-amylase (α-Amy), enzymes responsible for the hydrolysis of carbohydrates. In recent decades, many natural compounds and their bioinspired analogues have been studied as α-Glu and α-Amy inhibitors. However, no studies have been devoted to the evaluation of α-Glu and α-Amy inhibition by the neolignan obovatol (1). In this work, we report the synthesis of 1 and a library of new analogues. The synthesis of these compounds was achieved by implementing methodologies based on: phenol allylation, Claisen/Cope rearrangements, methylation, Ullmann coupling, demethylation, phenol oxidation and Michael-type addition. Obovatol (1) and ten analogues were evaluated for their in vitro inhibitory activity towards α-Glu and α-Amy. Our investigation highlighted that the naturally occurring 1 and four neolignan analogues (11, 22, 26 and 27) were more effective inhibitors than the hypoglycemic drug acarbose (α-Amy: 34.6 µM; α-Glu: 248.3 µM) with IC5O value of 6.2-23.6 µM toward α-Amy and 39.8-124.6 µM toward α-Glu. Docking investigations validated the inhibition outcomes, highlighting optimal compatibility between synthesized neolignans and both the enzymes. Concurrently circular dichroism spectroscopy detected the conformational changes in α-Glu induced by its interaction with the studied neolignans. Detailed studies through fluorescence measurements and kinetics of α-Glu and α-Amy inhibition also indicated that 1, 11, 22, 26 and 27 have the greatest affinity for α-Glu and 1, 11 and 27 for α-Amy. Surface plasmon resonance imaging (SPRI) measurements confirmed that among the compounds studied, the neolignan 27 has the greater affinity for both enzymes, thus corroborating the results obtained by kinetics and fluorescence quenching. Finally, in vitro cytotoxicity of the investigated compounds was tested on human colon cancer cell line (HCT-116). All these results demonstrate that these obovatol-based neolignan analogues constitute promising candidates in the pursuit of developing novel hypoglycemic drugs.

Fast and precise chiroptical spectroscopy by photoelectron elliptical dichroism.

The photoionization of chiral molecules by elliptically polarized femtosecond laser pulses produces photoelectron angular distributions which show a strong and enantio-sensitive forward/backward asymmetry along the light propagation direction. We report on high precision measurements of this photoelectron elliptical dichroism (PEELD). Using an optical cavity to recycle the laser pulses and increase the signal-to-noise ratio, we determine enantiomeric excesses with a 0.04% precision with a low-power femtosecond laser (4 W) in a compact scheme. We perform momentum-resolved PEELD measurements in 16 molecules, from volatile terpenes to non-volatile amino acids and large iodoarenes. The results demonstrate the high structural sensitivity of PEELD, confirming the spectroscopic interest of this technique. Last, we show how a convolutional neural network can be used to retrieve the chemical and enantiomeric composition of a sample from the momentum-resolved PEELD maps.

Synthesis of Flavonol-Bearing Probes for Chemoproteomic and Bioinformatic Analyses of Asteraceae Petals in Search of Novel Flavonoid Enzymes.

This study aimed at searching for the enzymes that are responsible for the higher hydroxylation of flavonols serving as UV-honey guides for pollinating insects on the petals of Asteraceae flowers. To achieve this aim, an affinity-based chemical proteomic approach was developed by relying on the use of quercetin-bearing biotinylated probes, which were thus designed and synthesized to selectively and covalently capture relevant flavonoid enzymes. Proteomic and bioinformatic analyses of proteins captured from petal microsomes of two Asteraceae species (Rudbeckia hirta and Tagetes erecta) revealed the presence of two flavonol 6-hydroxylases and several additional not fully characterized proteins as candidates for the identification of novel flavonol 8-hydroxylases, as well as relevant flavonol methyl- and glycosyltransferases. Generally speaking, this substrate-based proteome profiling methodology constitutes a powerful tool for the search for unknown (flavonoid) enzymes in plant protein extracts.

Asymmetric Allenylation of Alkynes mediated by Chiral Organoselenated Reagents under Oxidative Conditions.

The reactivity of novel chiral lactamide-substituted diselenide-based reagents under oxidative conditions was exploited to develop a metal-free method for the preparation of enantioenriched allenylamides from simple alkynes in good yields, and with enantiomeric excesses up to 99 %. The key of the success in this method is attributed to the hydrogen-bonded lactamide appendages that ensure configurational stability of chiral vinyl selenoxide intermediates for an optimal enantiotopic ß-syn-elimination step.

Real-Time Analysis of Polyphenol-Protein Interactions by Surface Plasmon Resonance Using Surface-Bound Polyphenols.

A selection of bioactive polyphenols of different structural classes, such as the ellagitannins vescalagin and vescalin, the flavanoids catechin, epicatechin, epigallocatechin gallate (EGCG), and procyanidin B2, and the stilbenoids resveratrol and piceatannol, were chemically modified to bear a biotin unit for enabling their immobilization on streptavidin-coated sensor chips. These sensor chips were used to evaluate in real time by surface plasmon resonance (SPR) the interactions of three different surface-bound polyphenolic ligands per sensor chip with various protein analytes, including human DNA topoisomerase IIα, flavonoid leucoanthocyanidin dioxygenase, B-cell lymphoma 2 apoptosis regulator protein, and bovine serum albumin. The types and levels of SPR responses unveiled major differences in the association, or lack thereof, and dissociation between a given protein analyte and different polyphenolic ligands. Thus, this multi-analysis SPR technique is a valuable methodology to rapidly screen and qualitatively compare various polyphenol-protein interactions.

Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus.

There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could be a strategy to impede viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that was previously demonstrated to be active against Influenza A virus, were evaluated against SARS-CoV-2. Intrinsic fluorescence spectroscopy, fluorescence anisotropy, and dynamic light scattering assays demonstrated naproxen binding to the nucleoprotein of SARS-Cov-2 as predicted by molecular modeling. Naproxen impeded recombinant N oligomerization and inhibited viral replication in infected cells. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage. No inhibition of viral replication was observed with paracetamol or the COX-2 inhibitor celecoxib. Thus, among the NSAID tested, only naproxen combined antiviral and anti-inflammatory properties. Naproxen addition to the standard of care could be beneficial in a clinical setting, as tested in an ongoing clinical study.

Bispericyclic Diels-Alder Dimerization of ortho-Quinols in Natural Product (Bio)Synthesis: Bioinspired Chemical 6-Step Synthesis of (+)-Maytenone.

Many natural products of plant or microbial origins are derived from enzymatic dearomative oxygenation of 2-alkylphenolic precursors into 6-alkyl-6-hydroxycyclohexa-2,4-dienones. These so-called ortho-quinols cyclodimerize via a remarkably selective bispericyclic Diels-Alder reaction. Whether or not the intervention of catalytic or dirigent proteins is involved during this final step of the biosynthesis of these natural products, this cyclodimerization of ortho-quinols can be chemically reproduced in the laboratory with the same strict level of site-specific regioselectivity and stereoselectivity. This unique yet unified process, which finds its rationale in the inherent chemical reactivity of those ortho-quinols, is illustrated herein by an efficient and bioinspired first chemical synthesis of one of the most structurally complex and synthetically challenging examples of such natural cyclodimers, the bisditerpenoid (+)-maytenone.

Synthesis and leishmanicidal evaluation of sulfanyl- and sulfonyl-tethered functionalized benzoate derivatives featuring a nitroimidazole moiety.

A series of new nitroimidazole-containing derivatives was synthesized by coupling of 2-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio]ethanol with diversely substituted benzoic acids. Upon treatment with m-CPBA, 12 of these sulfanyl compounds were further oxidized to their sulfonyl analogs. All the 26 synthetic compounds were examined for in vitro activity against Leishmania (V.) braziliensis and Leishmania (L.) mexicana, and some of them displayed an efficient antileishmanial activity. Among the compounds tested, the catecholic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4-dihydroxybenzoate (9a, LC50 = 13 and 11 µM) and the pyrogallolic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4,5-trihydroxybenzoate (9b, LC50 = 4 and 1 µM) were the most active ones against the two Leishmania strains.

Synthesis of [7]Helicene Enantiomers and Exploratory Study of Their Conversion into Helically Chiral Iodoarenes and Iodanes.

The facile and convenient preparation of both enantiomers of a [7]helicene scaffold from inexpensive (l)-(+)-tartaric acid and 4-methylstyrene is described. These helical structures were transformed into bis-iodinated ether derivatives in order to explore their potential as precursors of novel chiral organoiodane reagents or as iodoarene pre-catalysts. Promising results were obtained in hydroxylative phenol dearomatization/[4+2] cycloaddition cascade and dearomative spirolactonization reactions with encouraging enantiomeric excesses.

Bio-inspired Total Synthesis of Twelve Securinega Alkaloids: Structural Reassignments of (+)-Virosine†B and (-)-Episecurinol†A.

The so-called Securinega alkaloids constitute a class of tetracyclic biologically active specialised metabolites isolated principally from subtropical plants belonging to the Phyllanthaceae family. Following a strategy based on alternative hypotheses for their biosynthesis, an easy and time-efficient divergent synthesis enabled access to twelve of those alkaloids featuring (neo)(nor)securinane skeletons. Moreover, this work permitted to reassign the absolute configurations of (+)-virosine B and (-)-episecurinol A.

Blue LED Irradiation of Iodonium Ylides Gives Diradical Intermediates for Efficient Metal-free Cyclopropanation with Alkenes.

A facile and highly chemoselective synthesis of doubly activated cyclopropanes is reported where mixtures of alkenes and ß-dicarbonyl-derived iodonium ylides are irradiated with light from blue LEDs. This metal-free synthesis gives cyclopropanes in yields up to 96 %, is operative with cyclic and acyclic ylides, and proceeds with a variety of electronically-diverse alkenes. Computational analysis explains the high selectivity observed, which derives from exclusive HOMO to LUMO excitation, instead of free carbene generation. The procedure is operationally simple, uses no photocatalyst, and provides access in one step to important building blocks for complex molecule synthesis.

Asymmetric Alkynylation of ß-Ketoesters and Naphthols Promoted by New Chiral Biphenylic Iodanes.

The preparation of new chiral biphenylic λ3 -iodane reagents bearing transferable alkynyl ligands is described. These reagents transfer their carbon-based ligands onto ß-ketoesters with an enantiomeric excess (ee) up to 68 %, and most remarkably, enable the dearomative alkynylation of naphthols in good to high yields up to 84 % ee.

ortho-Quinol Acetate Chemistry: Reactivity toward Aryl-Based Nucleophiles and Applications to the Synthesis of Natural Products.

Two model ortho-quinol acetates were easily prepared by iodane-mediated acetoxylative phenol dearomatization and evaluated for their reactivity toward various aryl-based nucleophiles, i.e., aryl metallic reagents and phenolic derivatives. Novel modes of reactivity, allowing the formation of biaryl linkages, were revealed and here exploited for the synthesis of two natural phenolics.

Synthesis of Scyphostatin Analogues through Hypervalent Iodine-Mediated Phenol Dearomatization.

A concise synthesis of two scyphostatin analogues is achieved from readily available ortho-substituted phenols. Key features include an asymmetric and biomimetic hydroxylative phenol dearomatization (HPD) reaction promoted by a chiral salen-type bis(λ5-iodane) reagent, followed by an in situ regio- and diastereocontrolled epoxidation.

Bioinspired Total Synthesis of (-)-Vescalin: A Nonahydroxytriphenoylated C-Glucosidic Ellagitannin.

The first total synthesis of the 2,3,5-O-(S,R)-nonahydroxytriphenoylated (NHTP) C-glucosidic ellagitannin (-)-vescalin was accomplished through a series of transformations mimicking the sequence of events leading to its biogenesis. The key steps of this synthesis encompass a Wittig-mediated ring opening of a glucopyranosic hemiacetal, a C-glucosidation event through a phenolic aldol-type reaction, and a Wynberg-Feringa-Yamada-type oxidative phenolic coupling, which forged the NHTP unit of (-)-vescalin.

Phenol Dearomatization with Hypervalent Iodine Reagents.

This chapter highlights recent developments in phenol dearomatization using organoiodane reagents and a selection of applications in natural product synthesis.

Gallotannins and Tannic Acid: First Chemical Syntheses and In Vitro Inhibitory Activity on Alzheimer's Amyloid ß-Peptide Aggregation.

The screening of natural products in the search for new lead compounds against Alzheimer's disease has unveiled several plant polyphenols that are capable of inhibiting the formation of toxic ß-amyloid fibrils. Gallic acid based gallotannins are among these polyphenols, but their antifibrillogenic activity has thus far been examined using "tannic acid", a commercial mixture of gallotannins and other galloylated glucopyranoses. The first total syntheses of two true gallotannins, a hexagalloylglucopyranose and a decagalloylated compound whose structure is commonly used to depict "tannic acid", are now described. These depsidic gallotannins and simpler galloylated glucose derivatives all inhibit amyloid ß-peptide (Aß) aggregation in vitro, and monogalloylated α-glucogallin and a natural ß-hexagalloylglucose are shown to be the strongest inhibitors.

Asymmetric hydroxylative phenol dearomatization promoted by chiral binaphthylic and biphenylic iodanes.

The long-standing quest for chiral hypervalent organoiodine compounds (i.e., iodanes) as metal-free reagents for asymmetric synthesis continues. Although remarkable progress has recently been made in organoiodine-catalyzed reactions using a terminal oxidant in stoichiometric amounts, there is still a significant need for "flaskable" chiral iodane reagents. Herein, we describe the synthesis of new iodobinaphthyls and iodobiphenyls, their successful and selective DMDO-mediated oxidation into either λ(3)- or λ(5)-iodanes, and the evaluation of their capacity to promote asymmetric hydroxylative phenol dearomatization (HPD) reactions. Most notably, a C2-symmetrical biphenylic λ(5)-iodane promoted the HPD-induced conversion of the monoterpene thymol into the corresponding ortho-quinol-based [4+2] cyclodimer (i.e., bis(thymol)) with enantiomeric excesses of up to 94%.

Total Synthesis of the Bacterial ortho-Quinol (+)-Strepantibin A through Iodyl-Type λ5-Iodane-Promoted Asymmetric Hydroxylative Phenol Dearomatization.

An enantioselective synthesis of the bacterial metabolite (+)-strepantibin A, a novel inhibitor of the hexokinase II (HK2) in cancer cells, is described. Its monomethylated resorcinolic para-terphenyl core was conveniently prepared through a Danheiser benzannulation. The elaboration of its ortho-quinolic chiral center was accomplished by relying on an iodyl-promoted regio- and enantioselective hydroxylative dearomatization. The olefinic side-chain of the resulting ortho-quinol was finally oxygenated under Wacker-type conditions to generate the propanone appendage of (+)-strepantibin A.

Remarkable biomimetic chemoselective aerobic oxidation of flavano-ellagitannins found in oak-aged wine.

Under the auspices of Bacchus! Acutissimins, natural flavano-ellagitannins, occur in oak-aged wine as a result of a diastereoselective condensation reaction of the flavan-3-ol catechin, a component of grapes, with the C-glucosidic ellagitannin vescalagin, found in oak. The acutissimins are further converted into natural mongolicains and analogues of camelliatannin G in a remarkably chemoselective fashion by simple aerobic oxidation.