Enantiopure [6]-Azairidahelicene by Dynamic Kinetic Resolution of a Configurationally Labile [4]-Helicene.

A pair of enantiopure [6]-azairidahelicenes incorporating chirality at the metal center and on the helicenic ligand were synthesized by dynamic kinetic resolution (dkr) of a configurationally labile [4]-helicenic ligand (4-(2-pyridyl)-benzo[g]phenanthrene, L1H) using bis-cyclometalated chiral-at-metal only iridium(III) precursors as chiral inductors. The origin of the observed dkr is attributed to the different conformation and stability of diastereomeric reaction intermediates formed during the cyclometalation process. The isolated enantiomers exhibited circularly polarized phosphorescence (CPP), with |gphos| values of 1.8×10-3.

Dehydration of alcohols catalyzed by copper(II) sulfate: type II dyotropic reactions and stepwise mechanisms.

Dehydration of alcohols in the presence of copper(II) sulfate has been analyzed computationally. Density functional theory (DFT) calculations on selected alcohols indicate that this reaction can take place via two possible mechanisms: (a) concerted - although asynchronous - type II dyotropic reactions, or (b) stepwise E1-like processes, in which cleavage of the C-O bond occurs in the first step, followed by syn proton elimination. Our calculations show the relationship between the initial alcohol structure and the preferred mechanism, which is a type II dyotropic reaction for primary alcohols, whereas a stepwise process is the favored one when stable carbocation intermediates are energetically accessible. The dehydration of dehydrolinalool (2,7-dimethyl-6-en-1-yn-3-ol, DHL) to yield different alkenes of interest in the fragrance industry is discussed as a case study of its regiochemistry.

Higher-Order Electrocyclizations in Biological and Synthetic Processes.

In general, electrocyclizations follow the Woodward-Hoffmann's rules of conservation of orbital symmetry. These rules have been extensively verified in low-order processes, both in thermal and photochemical reactions, up to eight π-electrons. However, when the number of π-electrons in the system increases, some deviations of that general rules can be found. This focused review highlights the main features of reported higher-order electrocyclizations involving 10, 12, 14, 16 and 18 π-electrons. Some of these examples constitute useful intermediates in the synthesis of biologically active compounds. When computational studies were not included in the reported examples, DFT calculations have been performed to be included in this review. Analysis of the respective pericyclic topologies shows the importance of computational tools for understanding the selectivity observed experimentally.

Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis.

BACKGROUND: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. METHODS: Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. RESULTS: A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs-15 studies), perihilar-distal CCAs (p/dCCAs-7 studies), and gallbladder cancer (GBC-5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. CONCLUSION: From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.

Aromaticity: Quo Vadis.

Aromaticity is one of the most deeply rooted concepts in chemistry. But why, if two-thirds of existing compounds can be classified as aromatic, is there no consensus on what aromaticity is? σ-, π-, δ-, spherical, Möbius, or all-metal aromaticity… why are so many attributes needed to specify a property? Is aromaticity a dubious concept? This perspective aims to reflect where the aromaticity community is and where it is going.

Selectivity in Cationic Cyclizations Involving Alkynes: A Computational Study on the Biomimetic Synthesis of Steroids.

Invited for the cover of this issue are Abel de Cózar, Ana Arrieta and Fernando P. Cossío at the University of the Basque Country. The image depicts the evolution of a reactive cation to the corresponding cyclic intermediate in the course of a regio- and stereocontrolled biomimetic cyclization. Read the full text of the article at 10.1002/chem.202204028.

Selectivity in Cationic Cyclizations Involving Alkynes: A Computational Study on the Biomimetic Synthesis of Steroids.

Computational studies on the electrophilic cyclization between alkynes and transient carbocations or Lewis-acid-activated epoxides show that the regiochemistry of the reaction depends on the terminal or internal position of the triple bond. Reactants possessing terminal alkynyl groups lead to six-membered rings, whereas internal alkynes yield five-membered rings through 6-endo-dig and 5-exo-dig electrophilic cyclizations, respectively. The regiochemistry of the reaction is not determined by two-electron interactions, but by the minimization of Pauli repulsion. This scenario is preserved in related biomimetic reactions leading to steroid scaffolds. In this latter case, the stereochemistry of the cyclization reaction is oriented towards the formation of equatorial C-C bonds connecting the new six-six- and six-five-membered fused rings.

Synthesis of Bicyclic Hemiacetals Catalyzed by Unnatural Densely Substituted γ-Dipeptides.

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.

Phenanthrene-Extended Phenazine Dication: An Electrochromic Conformational Switch Presenting Dual Reactivity.

The synthesis and isolation of one of the few examples of a π-extended diamagnetic phenazine dication have been achieved by oxidizing a phenanthrene-based dihydrophenazine precursor. The resulting dication was isolated and fully characterized, highlighting an aromatic distorted structure, generated by the conformational change upon the oxidation of the dihydrophenazine precursor, which is also correlated with a marked electrochromic change in the UV-vis spectrum. The aromaticity of the dication has also been investigated theoretically, proving that the species is aromatic based on all major criteria (structural, magnetic, and energetic). Moreover, the material presents an intriguing dual reactivity, resulting in ring contraction to a π-extended triarylimidazolinium and reduction to the dihydrophenazine precursor, depending on the nature of the nucleophile involved. This result helps shed light on the yet largely unexplored reactivity and properties of extended dicationic polycyclic aromatic hydrocarbons (PAHs). In particular, the fact that the molecule can undergo a reversible change in conformation upon oxidation and reduction opens potential applications for this class of derivatives as molecular switches and actuators.

A Synthetic Analog of Resveratrol Inhibits the Proangiogenic Response of Liver Sinusoidal Cells during Hepatic Metastasis.

We utilized Fas21, a resveratrol analog, to modulate the function of hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the angiogenic phase of murine liver metastasis by B16 melanoma and 51b colorectal carcinoma. Preangiogenic micrometastases were treated with Fas21 (1 mg/kg/day) or vehicle during the development of intra-angiogenic tracts. Mice treated with Fas21 showed reduced liver tumor foci in both liver metastasis models. Micrometastases were classified immunohistochemically, as well as according to their position coordinates and connection to local microvasculature. The volume of liver occupied by sinusoidal-type foci, containing infiltrating angiogenic capillaries, decreased by ~50% in Fas21-treated mice compared to vehicle-treated ones in both tumor metastasis models. The volume of portal foci, containing peripheral neoangiogenesis within a discontinuous layer of myofibroblasts, was similar in all experimental groups in both tumor metastasis models, but displayed enhanced necrotic central areas devoid of angiogenesis following Fas21 treatment. As a result, sinusoidal tumors from mice treated with Fas21 showed a 50% reduction in desmin(+)/asma(+) HSCs and CD31(+) vessel density, and a 45% reduction in intrametastatic VEGF mRNA compared with sinusoidal tumors from vehicle-treated mice. Necrotic portal metastases increased 2-4-fold in treated mice. In vitro, Fas21 reduced VEGF secretion by HSCs and 51b cells dose-dependently. Additionally, HSCs migration in response to tumor soluble factors was dose-dependently diminished by Fas21, as was LSEC migration in response to HSCs and tumor soluble factors. Resveratrol analog Fas21 inhibits the proangiogenic response of HSCs and LSECs during the development of murine liver metastasis.

Additive and Emergent Catalytic Properties of Dimeric Unnatural Amino Acid Derivatives: Aldol and Conjugate Additions.

Different densely substituted L- and D-proline esters were prepared by asymmetric (3+2) cycloaddition reactions catalyzed by conveniently selected EhuPhos chiral ligands. The γ-nitro-2-alkoxycarbonyl pyrrolidines thus obtained in either their endo or exo forms were functionalized and coupled to yield the corresponding γ-dipeptides. The catalytic properties of these latter dimers were examined using aldol and conjugate additions as case studies. When aldol reactions were analyzed, an additive behavior in terms of stereocontrol was observed on going from the monomers to the dimers. In contrast, in the case of the conjugate additions between ketones and nitroalkenes, the monomers did not catalyze this reaction, whereas the different γ-dipeptides promoted the formation of the corresponding Michael adducts. Therefore, in this latter case emergent catalytic properties were observed for these novel γ-dipeptides based on unnatural proline derivatives. Under certain conditions stoichiometric amounts of ketone, acid and nitroalkene), formation of N-acyloxy-2-oxooctahydro-1H-indoles was observed.

Bicolour fluorescent molecular sensors for cations: design and experimental validation.

Molecular entities whose fluorescence spectra are different when they bind metal cations are termed bicolour fluorescent molecular sensors. The basic design criteria of this kind of compound are presented and the different fluorescent responses are discussed in terms of their chemical behaviour and electronic features. These latter elements include intramolecular charge transfer (ICT), formation of intramolecular and intermolecular excimer/exciplex complexes and Förster resonance energy transfer (FRET). Changes in the electronic properties of the fluorophore based on the decoupling between its constitutive units upon metal binding are also discussed. The possibility of generating fluorescent bicolour indicators that can capture metal cations in the gas phase and at solid-gas interfaces is also discussed.

Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease.

BACKGROUND AND AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. APPROACH AND RESULTS: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. CONCLUSIONS: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.

Role of imine isomerization in the stereocontrol of the Staudinger reaction between ketenes and imines.

Computational-experimental analysis has allowed determining that the stereochemistry of the Staudinger reaction between ketenes and imines is strongly associated with the nature of the imine, which affects the two steps of the reaction. The first step, namely the nucleophilic attack of the sp2-hybridized nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene, is affected by the energetically accessible in situ isomerization patterns of the imine. The second step consists of a conrotatory electrocyclization of the zwitterionic intermediate formed in the previous step. This latter pericyclic step depends on the inward/outward torquoelectronic effects generated by the substituents of the imine. The impact of these factors on the stereochemistry of this reaction has been analyzed kinetically by numerical methods. The results of these simulations are compatible with the experimental results and support these conclusions.

Fluorescent Imidazo[1,2-a]pyrimidine Compounds as Biocompatible Organic Photosensitizers that Generate Singlet Oxygen: A Potential Tool for Phototheranostics.

Photodynamic therapy has been used to treat a variety of diseases, however, there is continuing search for new biocompatible photosensitizers. Herein, we demonstrate for the first time that imidazo[1,2-a]pyrimidine compounds are able to generate singlet oxygen species and can act as photosensitizers in the intracellular environment. Our results show that this class of compounds absorb and emit in the 400-500 nm region, present low cytotoxicity in the dark, are efficiently uptaken by cells, are fluorescent in intracellular medium, and generate singlet oxygen upon irradiation, killing cancer cells within 2 h at low concentration (2.0 µm). The imidazo[1,2-a]pyrimidine compounds are a potential new tool for phototheranostics, because they can be simultaneously used for fluorescence imaging and photodynamic therapy.

Towards a more precise therapy in cancer: Exploring epigenetic complexity.

A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.

Fluorescent bicolour sensor for low-background neutrinoless double ß decay experiments.

Observation of the neutrinoless double ß decay is the only practical way to establish that neutrinos are their own antiparticles1. Because of the small masses of neutrinos, the lifetime of neutrinoless double ß decay is expected to be at least ten orders of magnitude greater than the typical lifetimes of natural radioactive chains, which can mimic the experimental signature of neutrinoless double ß decay2. The most robust identification of neutrinoless double ß decay requires the definition of a signature signal-such as the observation of the daughter atom in the decay-that cannot be generated by radioactive backgrounds, as well as excellent energy resolution. In particular, the neutrinoless double ß decay of 136Xe could be established by detecting the daughter atom, 136Ba2+, in its doubly ionized state3-8. Here we demonstrate an important step towards a 'barium-tagging' experiment, which identifies double ß decay through the detection of a single Ba2+ ion. We propose a fluorescent bicolour indicator as the core of a sensor that can detect single Ba2+ ions in a high-pressure xenon gas detector. In a sensor made of a monolayer of such indicators, the Ba2+ dication would be captured by one of the molecules and generate a Ba2+-coordinated species with distinct photophysical properties. The presence of such a single Ba2+-coordinated indicator would be revealed by its response to repeated interrogation with a laser system, enabling the development of a sensor able to detect single Ba2+ ions in high-pressure xenon gas detectors for barium-tagging experiments.

Stepwise Mechanism for the Bromination of Arenes by a Hypervalent Iodine Reagent.

A mild, metal-free bromination method of arenes has been developed using the combination of bis(trifluoroacetoxy)iodobencene and trimethylsilyl bromide. In situ-formed dibromo(phenyl)-λ3-iodane (PhIBr2) is proposed as the reactive intermediate. This methodology using PIFA/TMSBr has been applied with success to a great number of substrates (25 examples). The treatment of mono-substituted activated arenes led to para-brominated products (2u-z) in excellent 83-96% yields. Density functional theory calculations indicate a stepwise mechanism involving a double bromine addition followed by a type II dyotropic reaction with concomitant re-aromatization of the six-membered ring.

Discovering Biomolecules with Huisgenase Activity: Designed Repeat Proteins as Biocatalysts for (3 + 2) Cycloadditions.

Designed repeat proteins catalyze the 1,3-dipolar reaction between an imine and a π-deficient dipolarophile in THF solution to form unnatural nitroproline esters, a reaction that no enzyme can catalyze. NMR studies and mutation experiments show that both acidic and basic residues can catalyze the reaction. The diastereocontrol of the reaction depends on the flexibility of the protein and on the number and location of the active lysine and glutamate residues, which can participate independently or forming dyads that promote the formation of unusual diastereomeric cycloadducts. QM/MM calculations permit one to rationalize the origins of this Huisgenase activity and of its diastereocontrol.

Selective synthesis of trisubstituted pyrroles through the reactions of alkynyl Fischer carbene complexes with oxazolones.

An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a-qvia 1,3-dipolar cycloaddition of Δ3-trifluoromethyloxazolones 2a-d with both chromium and tungsten alkynyl Fischer carbene complexes (1a-h) is described. An unexpected and unreported -CF3 group elimination process was observed in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be responsible for this phenomenon. The dipolar cycloaddition proceeded efficiently to produce a single regioisomer, which was unambiguously established through NMR and single-crystal X-ray diffraction studies. Nevertheless, the reaction of alkynyl carbenes bearing an α,ß,γ,δ-unsaturated moiety with excess oxazolone 2a produced a polycyclic compound 6 speculatively formed through a cascade reaction involving 1,6-, 1,4- and 1,2-nucleophilic addition steps.