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We report the synthesis, chemical properties, and disulfide bond-reducing performance of a dithiol called NACMEAA, conceived as a hybrid of two biologically relevant thiols: cysteine and cysteamine. NACMEAA is conveniently prepared from inexpensive l-cystine in an efficient manner. As a nonvolatile, highly soluble, and neutral compound at physiological pH with the first thiol p

The SARS-CoV-2 life cycle is strictly dependent on the environmental redox state that influences both virus entry and replication. A reducing environment impairs the binding of the spike protein (S) to the angiotensin-converting enzyme 2 receptor (ACE2), while a highly oxidizing environment is thought to favor S interaction with ACE2. Moreover, SARS-CoV-2 interferes with redox homeostasis in infected cells to promote the oxidative folding of its own proteins. Here we demonstrate that synthetic low molecular weight (LMW) monothiol and dithiol compounds induce a redox switch in the S protein receptor binding domain (RBD) toward a more reduced state. Reactive cysteine residue profiling revealed that all the disulfides present in RBD are targets of the thiol compounds. The reduction of disulfides in RBD decreases the binding to ACE2 in a cell-free system as demonstrated by enzyme-linked immunosorbent and surface plasmon resonance (SPR) assays. Moreover, LMW thiols interfere with protein oxidative folding and the production of newly synthesized polypeptides in HEK293 cells expressing the S1 and RBD domain, respectively. Based on these results, we hypothesize that these thiol compounds impair both the binding of S protein to its cellular receptor during the early stage of viral infection, as well as viral protein folding/maturation and thus the formation of new viral mature particles. Indeed, all the tested molecules, although at different concentrations, efficiently inhibit both SARS-CoV-2 entry and replication in Vero E6 cells. LMW thiols may represent innovative anti-SARS-CoV-2 therapeutics acting directly on viral targets and indirectly by inhibiting cellular functions mandatory for viral replication.

A practical and asymmetric synthesis of (R)-4-amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole, an enantiopure framework shared by most ergot alkaloids, was accomplished. Our method involves a Rh(i)-catalyzed 6-exo-trig intramolecular cyclization of an appropriate 4-pinacolboronic ester d-tryptophan aldehyde followed by the oxidation of the resulting secondary benzylic alcohol with a Cu(i)-ABNO catalyst and final deprotection under acidic conditions. This new procedure offers significant advantages over previous synthetic approaches, including brevity, mild reaction conditions, preservation of chiral integrity, and high overall yield and avoids the use of stoichiometric amounts of strongly basic and pyrophoric organometallic reagents.

Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook

Transition metal‐catalyzed C3‐alkylation of indoles and oxindoles with nonderivatized alcohols, by means of borrowing hydrogen (BH) activation of the alcohol substrates, avoids the use of environmentally unfriendly alkylating agents. Only water is formed as the byproduct, thus making the BH process atom‐economical and environmentally benign. Diverse homogeneous and heterogeneous transition‐metal catalysts, indoles and oxindoles, and nonderivatized alcohols can be used for this transformation, hence rendering the BH process promising for replacing those procedures that use traditional alkylating agents. Although some earlier literature is discussed, this review mainly covers the literature published since 2015.

Fiscal discipline is commonly evaluated on the basis of the debt–gross domestic product ratio, which exhibits a stock variable measured relative to a flow variable. This way of monitoring debt solvency is arguably not consistent with transversality conditions obtained from optimizing macroeconomic frameworks. In this paper, we consider a wealth-based sustainability index of government debt policy derived from a baseline endogenous growth model. We calculate the index from 1999 onward for countries in which the after-growth real interest rate is positive, consistently with the theoretical setup. Results are radically different from common wisdom. We show that the fiscal position is sustainable for both Germany and Italy, and strongly unsustainable for both Japan and France. Policy implications of our findings are discussed.

A general two-step approach to enantiopure bromotryptophans from unprotected bromoindoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with cyclic sulfamidates derived from enantiopure d -serine to form 4-, 5-, 6-, or 7-bromo- d -tryptophan and some other halogenated tryptophans in moderate yields but with complete regioselectivity. The bromotryptophan derivatives were deprotected using mild conditions.

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.

The concise and convergent total syntheses of (+)- and (-)-Fumimycin have been achieved by taking advantage of strategies for the asymmetric aza-Friedel-Crafts reaction of a highly substituted hydroquinone and

The first total synthesis of natural (-)-clavicipitic acid from γ,γ-dimethylallyltryptophan (DMAT), its biosynthetic precursor, is described. This is done by regio- and chemoselective, remote, nondirected C(sp

A novel two-step synthesis of N-butanoyl-l-glutathione (C4-GSH) was developed involving the chemical modification of the commercially available starting material l-glutathione (GSH). This process n...

A series of five fluorescent ligands (L1–L5) for anions were designed and synthesized. Urea, thiourea, and cyanoguanidine moieties were chosen as the binding groups, while 3,5-bis(trifluoromethyl)phenyl, coumarin, and BODIPY were used as the chromophores. The cyanoguanidines L3–L5 were promptly synthesized from corresponding thioureas using EDCI followed by reaction with cyanamide in the presence of triethylamine. The absorption and emission properties of the ligands L1–L5 were studied in CH3CN; their coordination properties towards phosphate, pyrophosphate, and hydroxide anions, together with binding constants were evaluated.

Pd(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage of two sp(2) C-H bonds followed by C-C bond formation, stereoselectively generates highly valuable Z-dehydrophenylalanine skeletons in a practical, versatile, and atom economical manner. In addition, a perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks through copper-catalyzed conjugate additions of boron, silicon, and hydride moieties.

The rapid and expedient assembly of three new classes of biheterocycles of biological interest, viz. indole–imidazoles 4, indole–pyrroles 6 and indole–triazoles 8 was accomplished using different combinations of tryptamines, 1,2-diaza-1,3-dienes, aldehydes, and/or alkynes as readily available building blocks. Twenty-six derivatives were thus prepared in excellent yields (up to 100 %). The products were screened for in-vitro biological studies. Some of these revealed promising anticancer activity against MCF7 and Caco-2 human tumor cell lines.

The modular and versatile synthesis of C4-substituted tryptophan derivatives by direct functionalization of easily available N-acetyl 4-boronate tryptophan methyl ester via transition metal-catalyzed and metal-mediated cross coupling reactions is described. The versatility of the chemistry is highlighted by the gram-scale synthesis of 4-boronated N-acetyl-tryptophan methyl ester and the rapid synthesis of C4-aryl, C4-alkyl, C4-cyano, C4-trifluoromethyl, C4-azido, and C4-hydroxy tryptophan derivatives. The utility of our methodology is illustrated through the quick approach to the tricyclic azepino indole skeleton embedded in many natural products.

The identification of the temporal scales related to market activities is crucial for understanding the dynamics of international crude oil prices. Standard analysis techniques fail in producing consistently good results due to the non-linear behaviour of the oil market. In this paper we propose an innovative approach based on the concurring application of a new non-linear data analysis method, Fast Iterative Filtering (FIF), and a multi-scale statistical analysis (Standardized Mean Test). This approach proves to be able to separate automatically crude oil price data into three components: a long term trend, an intermediate or middle period behaviour, and a transitory or short-run behaviour. The economic meaning of each component is clearly identified as: high frequency variations, caused by normal supply-demand disequilibrium; medium term fluctuations, driven by geopolitical, financial, and technological shocks; a low frequency trend reflecting the global business cycle. All these results make the proposed approach a more performing tool for analysing oil price data structure and dynamics. Such a method, if coupled with different prediction techniques (e.g., ARIMA, ARCH, etc., or ANN, SVM, etc.), can potentially show higher performance than existing hybrid models in forecasting crude oil prices.

Oxindoles display a diverse pattern of reactivity upon reaction with different classes of amino alcohols via the borrowing hydrogen process. Whereas the reaction with N-acetyl amino alcohols leads to C3 alkylation, the reaction with N-alkyl amino alcohols results in the formation of synthetically useful α-aryl-lactams via a remarkably facile oxindole ring-opening reaction. Reactions occurred with quantitative conversion and selectivity under relatively mild reaction conditions.

N-Acetyl ketimine generated from methyl 2-acetamidoacrylate was explored to develop an unprecedented domino aza-Friedel-Crafts/lactonization reaction with naphthols and phenols (including 5-hydroxyindoles). This novel method requires a catalyst loading of only 5 mol % of a phosphoric acid catalyst and provides a new series of 3-NHAc-naphtho- and benzofuranone derivatives bearing tetra-substituted stereogenic centers in moderate-to-good yields. The enantioselective variant using BINOL-derived phosphoric acids was also explored with 1-naphthol, providing the desired product with moderate enantioselectivities (up to 99:1 following recrystallization).

A copper-based catalytic technique for the regioselective hydroboration and hydrosilylation of dehydroalanine derivatives has been developed. This method introduces synthetically versatile boron and silicon groups, while simultaneously performing a catalytic anti-Markovnikov hydrofunctionalization of dehydroalanines and dehydropeptides for the synthesis of amino acids and peptides bearing unnatural side-chains. The products obtained were expediently converted into valuable nonproteinogenic amino acid building blocks for polypeptide synthesis.

The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.

A Pd(II)-catalyzed intramolecular oxidative C–H/C–H cross-coupling has been developed for the direct construction of valuable polycyclic heteroarene scaffolds. From a retrosynthetic point of view, the strategic formation of a C–C bond via C(sp2)–H/C(sp2)–H dehydrogenative coupling across C3,N-linked biheterocyclic precursors may be useful in de novo syntheses of indole-derived natural products and pharmaceuticals. The reaction exhibited good functional group/heterocycle tolerance, and a proposed mechanism involving an azoylpalladium complex is also supported.

We present the coupling of primary and secondary benzyl alcohols with indoles to form 3-benzylated indoles and H2O that is catalyzed, for the first time, by a complex of earth-abundant iron. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, sustainability, high functional-group tolerance, and amenability to gram-scale synthesis. On the basis of the preliminary experimental observations, we propose that the reaction proceeds through a borrowing hydrogen process.

This paper analyzes strategic interactions and contagion effects in the peripheral countries of a monetary union. Using game theory and cost-benefit analysis, the paper determines the set of equilibrium solutions under which country-specific shocks are transmitted to other member countries giving rise to contagion. Numerical simulations, obtained by a simple calibration of the model on some key Mediterranean countries of the Euro Zone, show the probabilities of contagion from Greece, Spain and Italy.

A Bronsted acid catalyzed bisindolization reaction with suitable α-amido acetals that tolerates a wide range of indoles is reported. The method allows rapid access to the biologically relevant bisindolyl ethanamine scaffold in good to excellent yields upon mild amide basic hydrolysis. In preliminary pharmacological studies, some of these compounds display cytotoxic activity in U937 cancer cells. The marine natural alkaloid 2,2-di(6′-bromo-3′-indolyl)-ethylamine was the most active compound and could be a lead candidate for further optimization. For the first time, the biological role of this brominated bisindole marine alkaloid is presented.

The synthetic efforts toward the concise synthesis of (-)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C-N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (-)-epi-indolactam V and its enantiomer have been accomplished.

Pd(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage of two sp2 C–H bonds followed by C–C bond formation, stereoselectively generates highly valuable Z-dehydrophenylalanine skeletons in a practical, versatile, and atom economical manner. In addition, a perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks through copper-catalyzed conjugate additions of boron, silicon, and hydride moieties.

Observations concerning the synthesis of substituted tryptamine derivatives starting from indoles and 1,n-amino alcohols via the borrowing hydrogen process are discussed. This catalytic, single-step, and modular approach to tryptamines and homotryptamines allows the synthesis of branched and nonbranched tryptamines as well as tryptamine-based natural products such as psilocin, bufotenin, and serotonin.

Observations concerning the synthesis of substituted tryptamine derivatives starting from indoles and 1,n-amino alcohols via the borrowing hydrogen process are discussed. This catalytic, single-step, and modular approach to tryptamines and homotryptamines allows the synthesis of branched and nonbranched tryptamines as well as tryptamine-based natural products such as psilocin, bufotenin, and serotonin.

An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin.

A facile synthetic approach to the direct preparation of various novel unnatural boronated protected tryptophans using a regio- and chemoselective electrophilic substitution of 4- and 5-boronated indoles with N-protected dehydroalanine is described. The gram-scale synthesis of two free tryptophan boronic acids is also reported.

The first (organo)catalytic method for regio- and chemoselective aza-Friedel–Crafts (FC) alkylation of indoles and pyrroles with commercially available methyl α-acetamidoacrylates has been discovered. It minimizes/eliminates common competing reactions that occur due to the high and multiatom-nucleophilic character of indole and pyrrole. Diverse quaternary α-amino acids were successfully prepared in good yield and high selectivity using low catalyst loading. The enantioselective variant using BINOL-derived phosphoric acids was also explored with indole providing the desired F–C alkylation product with moderate enantioselectivities.

A practical and efficient synthesis of 3-substituted hexahydropyrrolo[2,3-b]indole is described. The addition/cyclization of 3-substituted indoles with alpha,beta-dehydroamino esters in the presence of a Lewis acid provides hexahydropyrrolo[2,3-b]indole adducts in good yields and stereoselectivities. This approach has been applied to the concise synthesis of esermethole employing an appropriately substituted indole and an N-acyl dehydroamino ester.

The scope and limitations of using palladium-catalyzed cross-coupling reactions of diverse butyl metal species with two different 2-halopurines were evaluated. While tributylboranes reacted readily and regioselectively with both 2-chloro-6-dibenzylaminopurines and 2-iodo-6-chloropurines, all the other alkyl metal species were much less reactive and gave very poor yield and/or selectivity of the desired product. This protocol was applied to the synthesis of an important adenosine A(2A) receptor antagonist, ST1535.

The synthesis and anion binding studies of the new neutral receptor 1,1′-(2,2′-(4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(2-oxoethane-2,1-diyl))bis(3-(3,5-bis(trifluoromethyl)phenyl)urea) (L1) are reported. L1 is a macrocyclic ligand containing the 3,5-trifluoromethylphenylureido-binding fragment attached as a side arm on the tetraazacyclododecane. L1 is soluble in numerous organic solvents; the binding properties of L1 towards several simple anions (G) were investigated by NMR, UV–vis and fluorescence techniques in DMSO and CH3CN solutions. L1 is able to bind F− , Cl− and AcO− in both solvents; in addition, it binds Br− in CH3CN. Fluoride shows the highest constant values in the halide series (F− > Cl− > Br− ) and AcO− is the most strongly bound among all the anions investigated. L1 is able to signal the presence of the anions in solution by fluorescence change; in the case of acetate, this occurs in the visible range.

The introduction of unconventional monetary policy, pushing down the euro value, aims at strengthening the euro area, by increasing its competitiveness and boosting its economic growth. The goal of our paper is to offer a theoretical validation of these facts using a monetary union model in which a representative country and a common central bank strategically interact. The country can choose to stay in or opt out from the monetary union after a demand shock, while the central bank controls the exchange rate to preserve the stability of the union. Our main result is that the announcement of common exchange rate depreciation reduces the probability of a monetary union breakup.

A new and efficient synthetic protocol for the preparation of unsymmetrical difunctionalized cyclen and its close derivatives using a modified Ugi reaction (N-split Ugi) is described. The scope of this methodology is further extended by the successful use of various isocyanides, highly functionalized carboxylic acids, and aldehydes.

Author(s): Valitutti, Giovanni; Duranti, Andrea; Mor, Marco; Piersanti, Giovanni; Piomelli, Daniele; Rivara, Silvia; Tontini, Andrea; Tarzia, Giorgio; Traldi, Pietro

Author(s): Valitutti, Giovanni; Duranti, Andrea; Lodola, Alessio; Mor, Marco; Piersanti, Giovanni; Piomelli, Daniele; Rivara, Silvia; Tontini, Andrea; Tarzia, Giorgio; Traldi, Pietro

The selective C3-alkylation of indoles with N-protected ethanolamines involving the “borrowing hydrogen” strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.

Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson's disease (PD). We previously identified the triazolo-9H-purine, ST1535, as a potent A(2A)R antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω-1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω-1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A(2A)R was determined. Two compounds, (2-(3,3-dimethylbutyl)-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine (3 b) and 4-(6-amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)-2-methylbutan-2-ol (3 c), exhibited good affinity against A(2A)R (Ki =0.4 nM and 2 nM, respectively) and high in vitro metabolic stability (89.5% and 95.3% recovery, respectively, after incubation with HLM for two hours).

This paper applies game theory and a cost-benefit analysis to study voluntary exits and contagion effects in countries joined to a monetary union. The paper looks at two non-core or periphery countries of a large union and examines the role of structural asymmetries and strategic interactions as determinants of equilibrium outcomes, following both country-specific and common shocks. The paper finds that under almost symmetry between countries, country-specific shocks are never associated with multiple equilibria and, if large enough, can spread to other countries leading to contagion. By contrast, common shocks are seen to sustain multiple equilibria if almost-symmetric countries are considered and to have implications similar to those found in the country-specific case if large structural asymmetries are admitted.

We report our full account of the enantioselective total synthesis of (-)-acylfulvene (1) and (-)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late-stage reductive allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of (-)-acylfulvene (1) and (-)-irofulven (2).

An efficient and practical preparation of hydroxytyrosol and its orthogonally-protected forms was developed from inexpensive tyrosol. The utilization of Baeyer–Villiger oxidation enables the chemoselective introduction of a phenolic hydroxyl group in good yield.

A new and short synthesis of racemic cis-clavicipitic acid was achieved by taking advantage of the double nucleophilic character of indole-4-pinacolboronic ester. Key to the success of the synthesis were an efficient and selective C-3 indole Friedel–Crafts alkylation and the development of an unprecedented intramolecular rhodium-catalyzed 1,2-addition of an aryl pinacolboronic ester to an unactivated imine.