Substrate Selectivity Imparted by Self-Assembled Molecular Containers and Catalysts.

Recent trends in catalysis are devoted to mimicking some peculiar features of enzymes like site selectivity, through functional group recognition, and substrate selectivity, through recognition of the entire surface of the substrate. The latter is a specific feature of enzymes that is seldomly present in homogeneous catalysis. Supramolecular catalysis, thanks to the self-assembly of simple subunits, enables the creation of cavities and surfaces whose confinement effects drive the preferential binding of a substrate among others with consequent substrate selectivity. The topic is an emerging field that exploits recognition phenomena to discriminate the reagents based on their size and shape. This review deals this cutting-edge field of research covering examples of supramolecular self-assembled molecular containers and catalysts operating in organic as well as aqueous media, with special emphasis for catalytic systems dealing with direct competitive experiments involving two or more substrates.

In vitro binding analysis of legacy-linear and new generation-cyclic perfluoro-alkyl substances on sex hormone binding globulin and albumin, suggests low impact on serum hormone kinetics of testosterone.

In humans, serum testosterone (T) is largely bound to the sex hormone binding globulin (SHBG) and human serum albumin (hSA), resulting in a 2-3 % of unbound or "free" active quote (FT). Endocrine-disrupting chemicals, including perfluoro-alkyl substances (PFAS), are recognized to interfere with the hormonal axes, but the possible impact on the FT quote has not been addressed so far. Here we investigated the possible competition of two acknowledged PFAS molecules on T binding to SHBG and hSA. In particular, perfluoro-octanoic acid (PFOA) and acetic acid, 2,2-difluoro-2-((2,2,4,5-tetrafluoro-5(trifluoromethoxy)-1,3-dioxolan-4-yl)oxy)-ammonium salt (1:1) (C6O4) were used as, respectively, legacy-linear and new-generation-cyclic PFASs. Human recombinant SHBG 30-234 domain (SHBG30-234), produced in HEK293-F cells, and delipidated recombinant hSA were used as in vitro protein models. Isothermal Titration Calorimetry (ITC) and tryptophan fluorescence quencing (TFQ) were used to evaluate the binding modes of T and PFAS to SHBG30-234 and hSA. ITC revealed the binding of T to SHBG30-234 with a Kd of 44 ± 2 nM whilst both PFOA and C6O4 showed no binding activity. Results were confirmed by TFQ, since only T modified the fluorescence profile of SHBG30-234. In hSA, TFQ confirmed the binding of T on FA6 site of the protein. A similar binding mode was observed for PFOA but not for C6O4, as further verified by displacement experiments with T. Although both PFASs were previously shown to bind hSA, only PFOA is predicted to possibly compete with T for the binding to hSA. However, on the base of the binding stoichiometry and affinity of PFOA for hSA, this appears unlikely at the blood concentrations of the chemical documented to date.

A novel genetically-encoded bicyclic peptide inhibitor of human urokinase-type plasminogen activator with better cross-reactivity toward the murine orthologue.

The inhibition of human urokinase-type plasminogen activator (huPA), a serine protease that plays an important role in pericellular proteolysis, is a promising strategy to decrease the invasive and metastatic activity of tumour cells. However, the generation of selective small molecule huPA inhibitors has proven to be challenging due to the high structural similarity of huPA to other paralogue serine proteases. Efforts to generate more specific therapies have led to the development of cyclic peptide-based inhibitors with much higher selectivity against huPA. While this latter property is desired, the sparing of the orthologue murine poses difficulties for the testing of the inhibitor in preclinical mouse model. In this work, we have applied a Darwinian evolution-based approach to identify phage-encoded bicyclic peptide inhibitors of huPA with better cross-reactivity towards murine uPA (muPA). The best selected bicyclic peptide (UK132) inhibited huPA and muPA with Ki values of 0.33 and 12.58 µM, respectively. The inhibition appears to be specific for uPA, as UK132 only weakly inhibits a panel of structurally similar serine proteases. Removal or substitution of the second loop with one not evolved in vitro led to monocyclic and bicyclic peptide analogues with lower potency than UK132. Moreover, swapping of 1,3,5-tris-(bromomethyl)-benzene with different small molecules not used in the phage selection, resulted in an 80-fold reduction of potency, revealing the important structural role of the branched cyclization linker. Further substitution of an arginine in UK132 to a lysine resulted in a bicyclic peptide UK140 with enhanced inhibitory potency against both huPA (Ki = 0.20 µM) and murine orthologue (Ki = 2.79 µM). By combining good specificity, nanomolar affinity and a low molecular mass, the bicyclic peptide inhibitor developed in this work may provide a novel human and murine cross-reactive lead for the development of a potent and selective anti-metastatic therapy.

H2 Open - Guest Editorial.

This special collection presents original research articles and reviews that are connected to the multifaceted and rich chemistry of water. These works serve as an illustration of how, despite its apparent simplicity and ubiquity, water continues to be at the center of scientific exploration from a wide range of perspectives and employing the toolbox of modern-day chemistry.

Is Micellar Catalysis Green Chemistry?

Many years ago, twelve principles were defined for carrying out chemical reactions and processes from a green chemistry perspective. It is everyone's endeavor to take these points into account as far as possible when developing new processes or improving existing ones. Especially in the field of organic synthesis, a new area of research has thus been established: micellar catalysis. This review article addresses the question of whether micellar catalysis is green chemistry by applying the twelve principles to micellar reaction media. The review shows that many reactions can be transferred from an organic solvent to a micellar medium, but that the surfactant also has a crucial role as a solubilizer. Thus, the reactions can be carried out in a much more environmentally friendly manner and with less risk. Moreover, surfactants are being reformulated in their design, synthesis, and degradation to add extra advantages to micellar catalysis to match all the twelve principles of green chemistry.

A Safe-by-Design Approach to "Reef Safe" Sunscreens Based on ZnO and Organic UV Filters.

In recent years, the issue of coral bleaching has led to restrictions in some tropical locations (i.e., Palau, Hawaii, etc.) on the use of some organic UV sunscreen filters, such as oxybenzone and ethyl hexyl methoxycinnamate. In contrast, ZnO is considered safe for marine environments and thus is often used without considering its photocatalytic and oxidative activities related to the generation of O2•- and HO•. Moreover, ZnO needs to be used in combination with other filters to reach higher protection factors. Thus, the study of its interaction with formulations and with organic filters is important in sunscreen technology for the development of safer by-design products. In this work, the photocatalytic activity of zinc oxides with different surface areas (30, 25 and 9 m2/g) and their interaction with selected organic sunscreen filters were investigated. In particular, the ZnO photocatalytic kinetics were studied following the photodegradation of Acid Blue 9 (AB9) observing a first-order reaction with a chemical regime. Our evaluations of the selective inhibitions by hvb+ and HO• demonstrated a substantial predominance of the hydroxide radicals in the expression of the photocatalysis, a trend that was also confirmed by the irradiation of ZnO in an ethanolic solution. Indeed, the formulations containing both ZnO and organic filters defined as "safe" for coral reefs (i.e., Diethylamino Hydroxybenzoyl Hexyl Benzoate, DHHB, and Ethylhexyl Triazone, EHT) showed a non-negligible photocatalytic oxidation and thus the combination was underlined as safe to use.

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions.

The hexameric resorcin[4]arene capsule as a self-assembled organocatalyst promotes a series of reactions like the carbonyl-ene cyclization of (S)-citronellal preferentially to isopulegol, the water elimination from 1,1-diphenylethanol, the isomerization of α-pinene and ß-pinene preferentially to limonene and minor amounts of camphene. The role of the supramolecular catalyst consists in promoting the protonation of the substrates leading to the formation of cationic intermediates that are stabilized within the cavity with consequent peculiar features in terms of acceleration and product selectivity. In all cases the catalytic activity displayed by the hexameric capsule is remarkable if compared to many other strong Brønsted or Lewis acids.

Automatic classification of signal regions in 1H Nuclear Magnetic Resonance spectra.

The identification and characterization of signal regions in Nuclear Magnetic Resonance (NMR) spectra is a challenging but crucial phase in the analysis and determination of complex chemical compounds. Here, we present a novel supervised deep learning approach to perform automatic detection and classification of multiplets in 1H NMR spectra. Our deep neural network was trained on a large number of synthetic spectra, with complete control over the features represented in the samples. We show that our model can detect signal regions effectively and minimize classification errors between different types of resonance patterns. We demonstrate that the network generalizes remarkably well on real experimental 1H NMR spectra.

Modification of Amorphous Mesoporous Zirconia Nanoparticles with Bisphosphonic Acids: A Straightforward Approach for Tailoring the Surface Properties of the Nanoparticles.

The use of readily prepared bisphosphonic acids obtained in few steps through a thio-Michael addition of commercially available thiols on tetraethyl vinylidenebisphosphonate enables the straightforward surface modification of amorphous mesoporous zirconia nanoparticles. Simple stirring of the zirconia nanoparticles in a buffered aqueous solution of the proper bisphosphonic acid leads to the surface functionalization of the nanoparticles with different kinds of functional groups, charge and hydrophobic properties. Formation of both chemisorbed and physisorbed layers of the bisphosphonic acid take place, observing after extensive washing a grafting density of 1.1 molecules/nm2 with negligible release in neutral or acidic pH conditions, demonstrating stronger loading compared to monophosphonate derivatives. The modified nanoparticles were characterized by IR, XPS, ζ-potential analysis to investigate the loading of the bisphosphonic acid, FE-SEM to investigate the size and morphologies of the nanoparticles and 31 P and 1 H MAS NMR to investigate the coordination motif of the phosphonate units on the surface. All these analytical techniques demonstrated the strong affinity of the bisphosphonic moiety for the Zr(IV) metal centers. The functionalization with bisphosphonic acids represents a straightforward covalent approach for tailoring the superficial properties of zirconia nanoparticles, much straightforward compared the classic use of trisalkoxysilane or trichlorosilane reagents typically employed for the functionalization of silica and metal oxide nanoparticles. Extension of the use of bisphosphonates to other metal oxide nanoparticles is advisable.

Diketopyrrolopyrrole Bis-Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging.

The synthesis of a conjugate molecule between an unusual red-fluorescent diketopyrrolopyrrole (DPP) unit and a bis-phosphonate (BP) precursor by a click-chemistry strategy to target bone tissue and monitor the interaction is reported. After thorough investigation, conjugation through a triazole unit between a γ-azido rather than a ß-azido BP and an alkyne-functionalized DPP fluorophore group turned out to be the winning strategy. Visualization of the DPP-BP conjugate on osteoclasts and specific antiresorption activity were successfully demonstrated.

Selective Hydrogenations and Dechlorinations in Water Mediated by Anionic Surfactant-Stabilized Pd Nanoparticles.

We report a facile, inexpensive, and green method for the preparation of Pd nanoparticles in aqueous medium stabilized by anionic sulfonated surfactants sodium 1-dodecanesulfonate 1a, sodium dodecylbenzenesulfonate 1b, dioctyl sulfosuccinate sodium salt 1c, and poly(ethylene glycol) 4-nonylphenyl-3-sulfopropyl ether potassium salt 1d simply obtained by stirring aqueous solutions of Pd(OAc)2 with the commercial anionic surfactants further treated under hydrogen atmosphere for variable amounts of time. The aqueous Pd nanoparticle solutions were tested in the selective hydrogenation reactions of aryl-alcohols, -aldehydes, and -ketones, leading to complete conversion to the deoxygenated products even in the absence of strong Brønsted acids in the reduction of aromatic aldehydes and ketones, in the controlled semihydrogenation of alkynes leading to alkenes, and in the efficient hydrodechlorination of aromatic substrates. In all cases, the micellar media were crucial for stabilizing the metal nanoparticles, dissolving substrates, steering product selectivity, and enabling recycling. What is interesting is also that a benchmark catalyst like Pd/C can often be surpassed in activity and/or selectivity in the reactions tested by simply switching to the appropriate commercially available surfactant, thereby providing an easy to use, flexible, and practical catalytic system capable of efficiently addressing a variety of synthetically significant hydrogenation reactions.

Pyrrolidine-Containing Bisphosphonates as Potential Anti-Resorption Bone Drugs.

Bisphosphonates, particularly those with N-substituted groups, are currently the most popular drugs for the treatment of osteoporosis. However, their chemical structures are still rather simple and new synthetic methods are needed to expand their molecular complexity and also improve their specificity of action towards other targets as anticancer, antibacterial, and antimalarial drugs. Herein, we report a new class of potential antiresorption bisphosphonate drugs that have a pyrrolidine unit with different substituents, obtained through a simple dipolar cycloaddition reaction between azomethine ylides and vinylidenebisphosphonate derivatives as precursors. The methodology led to the efficient preparation of a wide range of (1-methylpyrrolidine-3,3-diyl)bis(phosphonic esters) derivatives with different substituents in position 4.

Substrate selective amide coupling driven by encapsulation of a coupling agent within a self-assembled hexameric capsule.

Encapsulation of a cationic carbodiimide condensing agent within a self-assembled hexameric capsule made of resorcin[4]arene units provides a nano-environment that efficiently steers the substrate selectivity in the amide synthesis reaction between carboxylic acids and primary amines. While in solution pairs of acids react similarly with a given amine, in the presence of the capsule the formation of the shorter amide is greatly favored.

Low toxicity and unprecedented anti-osteoclast activity of a simple sulfur-containing gem-bisphosphonate: a comparative study.

Bisphosphonates (BPs) are key drugs for the treatment of bone resorption diseases like osteoporosis, Paget's disease and some forms of tumors. Recent findings underlined the importance of lipophilic N-containing BPs to ensure high biological activity. Herein we present some unprecedented results concerning the low toxicity and good anti-osteoclast activity of low molecular weight hydrophilic S-containing BPs. A series of S and N-containing BPs bearing aromatic and aliphatic substitution were prepared through Michael addition reaction between vinylidenebisphosphonate tetraethyl ester and the proper nucleophile under basic catalysis. S-containing BPs showed a generally low toxicity, determined with the neutral-red assay using the L929 cell line, and, in particular for an aliphatic one, a good biological activity assessed on primary cultures of human osteoclasts.

Efficient isonitrile hydration through encapsulation within a hexameric self-assembled capsule and selective inhibition by a photo-controllable competitive guest.

Catalytic hydration of neutral isonitriles to yield the corresponding N-formylamides was achieved by reversible encapsulation in a self-assembled hexameric resorcin[4]arene capsule. Encapsulation of a photochromic dithienylethene bis-cation provides different levels of competitive inhibition depending on the geometry assumed by the cationic inhibitor.

Chiral M3L2 self-assembled capsules through metal coordination of enantiopure ligating benzocyclotrimers: NMR spectroscopic and ESI mass spectrometric investigation.

The synthesis of enantiopure (+)-benzotricamphor syn-5, an important chiral C3-symmetric rigid building block for supramolecular applications, was studied in detail to reduce the number of steps and to increase the diastereoselectivity and overall yield. The new synthetic procedure allowed larger amounts of syn-5 to be obtained and used for the preparation of new derivatives, such as the corresponding tris-trifluoromethanesulfonate syn-12, which was efficiently transformed into (+)-benzotribornenetrinitrile syn-1 and (+)-benzotribornenetris(ethynyl-4-pyridine) syn-2. The previously reported (+)-benzotricamphortrioxime syn-6 was transformed into tris-nitrile syn-3 by Beckman reaction. Compounds syn-1-3 were employed as multidentate ligands for silver(I) and platinum(II) centres in apolar solvents. The linear coordination geometry of Ag(I) and square-planar geometry of cis-chelated Pt(II) in combination with the chiral tripodal ligands syn-1-3 led to the formation of chiral enantiopure capsules with M3 L2 stoichiometry, as confirmed by 2D NMR NOESY and DOSY experiments as well as ESI mass spectrometry.

Switching the activity of a photoredox catalyst through reversible encapsulation and release.

Reversible encapsulation of [Ru(bpy)(3)](2+) within a self-assembled hexameric resorcin[4]arene capsule turns off the photocatalytic aerobic oxidation of an aliphatic sulfide. Upon addition of a competitive cationic guest, the Ru(II) catalyst is released into solution where its catalytic activity is restored.

Supramolecular control on chemo- and regioselectivity via encapsulation of (NHC)-Au catalyst within a hexameric self-assembled host.

The encapsulation of a Au(I) catalyst within a self-assembled, hydrogen bonded, hexameric capsule dramatically changes its catalytic activity, leading to unusual products due to the steric requirements of the host's cavity.

Gases as guests in benzocyclotrimer cage hosts.

An imine-linked (+)-syn-benzotricamphor derivative gives access to chiral unimolecular cages exhibiting internal cavities of new shapes and volumes. One of these hosts hydrocarbon gases at low temperatures in solution through CH-pi attractive interactions. No encapsulation is observed when the cage structure is too narrow or too large for the guest.