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Anionic 1,4-dihydro-1,4-diphosphinines were synthesized from tricyclic 1,4-diphosphinines and isolated as blue powdery salts M[

A nanocrystalline TiO2 dye-sensitized solar cell device consisting of dye 2 and fabricated with commercially available materials reaches a conversion efficiency of η = 1.20%. Dye 2 is a low-cost and easily prepared copper(i) molecular sensitizer.

Hypoxia-inducible factor-1alpha (HIF-1alpha) constitutes the principal mediator of cellular adaptation to hypoxia in humans. Hydroxylation of proline residues on HIF-1alpha is recognized by the E3 ligase von Hippel-Lindau (VHL), leading to ubiquitin-dependent proteasomal degradation of HIF-1alpha. In this study, we performed a structure-guided and bioactivity-driven design of new VHL inhibitors with improved cellular activity at blocking HIF-1alpha degradation. With the prototypical ligand VH298 as starting point, our iterative and combinatorial optimization strategy focused on introducing chemical variability into the phenylene unit of the VHL ligand structure and encompassed further points of diversity. The exploitation of tailored phenylene fragments combined with the stereoselective installation of the (S)-configured methyl group at the benzylic position provided VHL ligands with superior binding affinity compared to VH298. Three high-resolution structures of VHL in complex with three new ligands were determined and bioactive conformations of these ligands were explored. The most potent inhibitor (compound 30) exhibited dissociation constants (Kd) lower than 40 nM, independently determined by fluorescence polarization (FP) and surface plasmon resonance (SPR). The improved binding affinity to VHL was accompanied by enhanced cellular potency of 30, considerably exceeding the stabilization of HIF-1alpha by established VHL inhibitors. Our work is anticipated to inspire future efforts towards HIF-1alpha stabilizers and our optimized ligands to serve as an excellent starting point for proteolysis-targeting chimeras (PROTACs) hijacking VHL.

Although 1,2σ5λ5-oxaphosphetanes have been known for a long time, the “low-coordinate” 1,2σ3λ3-oxaphosphetanes have only been known since their first synthesis in 2018 via decomplexation. Apart from ligation of this P-heterocycle to gold(I)chloride and the oxidation using ortho-chloranil, nothing on their chemistry has been reported so far. Herein, we describe the synthesis of new 1,2σ3λ3-oxaphosphetane complexes (3a–e) and free derivatives (4a–e), as well as reactions of 4a with chalcogens and/or chalcogen transfer reagents, which yielded the P-chalcogenides (14–16a; Ch = O, S, Se). We also report on the theoretical results of the reaction pathways of C-phenyl-substituted 1,2 σ3λ3-oxaphosphetanes and ring strain energies of 1,2σ4λ5-oxaphosphetane P-chalcogenides.

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Solution-processed and thermally annealed thin films from a series of nalkyl terminated anilino squaraines are systematically investigated regarding their structural and optical properties by means of X-ray diffraction (XRD) and spectroscopic ellipsometry (SE). Their characteristic intense double-hump-shaped absorbance spectra consisting of coupled H-aggregate and intermolecular charge transfer (ICT) resonance bands make them appealing for fundamental light−matter interaction studies, and their environmental sustainability invites for consumer optoelectronic applications. Now, the single-crystal structure of the n-pentyl anilino squaraine (nPSQ) provides a missing link to identify potential odd−even effects with respect to the terminal alkyl chain for bulk crystals. While all single crystals adopt a triclinic unit cell with biaxial dielectric properties, the thin films condense into effectively uniaxial anisotropic thin films. Here, the inherently low sensitivity to the ut-ofplane complex refractive index of SE in reflection is reasonably compensated by adding transmission SE and transmission intensity data. With that, a general picture of the structural and dielectric properties of n-alkyl anilino squaraine thin films is launched, revealing that the terminal alkyl chain length affects the structural and optical properties in a twofold way: we observe a steady change which is superimposed by an anisotropic odd−even effect.

Five ligands with either nitrile or isonitrile metal binding motifs have been synthesized based on the 2,8- or 3,9-disubstituted Troger's base scaffold, respectively. These ligands self-assemble into dinuclear cyclic metallosupramolecular aggregates upon coordination to [(dppp)Pd(OTf)2 ] in a highly diastereoselective manner, by heterochiral self-sorting in a chiral self-discriminating manner as shown by ESI mass spectrometry, NMR spectroscopy, and single crystal XRD analysis. This observation is in contrast to earlier studies with ligands derived from Troger's base that have larger metal binding motifs and bis(nitrile) and bis(isonitrile) ligands based on other rigid dissymmetric cores such as [2.2]paracyclophanes. Thus, the combination of these slim metal binding motifs with the rigid v-shaped 2,8- or 3,9-disubstituted Troger's base scaffolds seems to be especially well preorganized to ensure high-fidelity social self-sorting behavior.

A new, mild and efficient protocol for the synthesis of trifluoromethyl(indolyl)phenylmethanols by the reaction of indoles with a variety of aromatic fluoromethyl ketones in the presence of K2CO3 (15 mol %) and n-Bu4PBr (15 mol %) in water. The desired products were obtained in good to excellent yields without requiring a column chromatographic purification. The reusability of the catalytic system and large-scale synthesis of indolyl(phenyl)methanols, which would further transform into biological active indole-derived compounds, are further advantages of this protocol.

Two isostructural ligands with either nitrile (Lnit) or isonitrile (Liso) moieties directly connected to a [2.2]paracyclophane backbone with pseudo‐meta substitution pattern have been synthesized. The ligand itself (Lnit) or its precursors (Liso) were resolved by HPLC on a chiral stationary phase and the absolute configuration of the isolated enantiomers was assigned by XRD analysis and/or by comparison of quantum‐chemical simulated and experimental electronic circular dichroism (ECD) spectra. Surprisingly, the resulting metallosupramolecular aggregates formed in solution upon coordination of [(dppp)Pd(OTf)2] differ in their composition: whereas Lnit forms dinuclear complexes, Liso exclusively forms trinuclear ones. Furthermore, they also differ in their chiral self‐sorting behavior as (rac)‐Liso undergoes exclusive social self‐sorting leading to a heterochiral assembly, whereas (rac)‐Liso shows a twofold preference for the formation of homochiral complexes in a narcissistic self‐sorting manner as proven by ESI mass spectrometry and NMR spectroscopy. Interestingly, upon crystallization, these discrete aggregates undergo structural transformation to coordination polymers, as evidenced by single‐crystal X‐ray diffraction., Two isostructural ligands with either nitrile (Lnit) or isonitrile (Liso) moieties attached to a [2.2]paracyclophane backbone have been synthesized. Surprisingly, the resulting discrete metallosupramolecular aggregates formed in solution upon coordination of [(dppp)Pd(OTf)2] differ in their composition and in their chiral self‐sorting behavior. Upon crystallization these discrete aggregates undergo structural transformation to coordination polymers.

Diels-Alder-reactions of a thiazol-2-thione-based, tricyclic 1,4-di-phosphinine were investigated, showing that the central aromatic π-system can react with various dienophiles. The reaction with 4-phenyl-1,2,4-triazoline-3,5-dione was special as the product revealed a remarkable sensitivity towards light, thus enabling the photochemical deprotection of the tricyclic 1,4-diphosphinine.

Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAFV600E mutation. First-generation BRAF inhibitors could lead to paradoxical activation of the MAPK pathway, limiting their clinical usefulness. Here, we show the development of two series of BRAF-targeting PROTACs and demonstrate that the exchange of the inhibitor scaffold from vemurafenib to paradox-breaker ligands resulted in BRAF degraders that did not cause paradoxical ERK activation. Članek objavljen 5. maja 2022. Nasl. z nasl. zaslona. Opis vira z dne 6. 5. 2022. Članek vsebuje supplement informacijo, [49 str.] Bibliografija: str. 735-736. Abstract. Cancer Research UK programme ARRS, program, P1-0208 ARRS

Naturally occurring compounds represent a vast pool of pharmacologically active entities. One of such compounds is andrographolide, which is endowed with many beneficial properties, including the activity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti-SARS-CoV-2 effects by inhibiting the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger on-target activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID-19 therapies.

Prototypical n-alkyl terminated anilino squaraines for photovoltaic applications show characteristic double-hump absorption features peaking in the green and deep-red spectral range. These signatures result from coupling of an intramolecular Frenkel exciton and an intermolecular charge transfer exciton. Crystalline, textured thin films suitable for polarized spectro-microscopy have been obtained for compounds with n-hexyl (nHSQ) and n-octyl (nOSQ) terminal alkyl chains. The here released triclinic crystal structure of nOSQ is similar to the known nHSQ crystal structure. Consequently, crystallites from both compounds show equal pronounced linear dichroism with two distinct polarization directions. The difference in polarization angle between the two absorbance maxima cannot be derived by spatial considerations from the crystal structure alone but requires theoretical modeling. Using an essential state model, the observed polarization behavior was discovered to depend on the relative contributions of the intramolecular Frenkel exciton and the intermolecular charge transfer exciton to the total transition dipole moment. For both nHSQ and nOSQ, the contribution of the charge transfer exciton to the total transition dipole moment was found to be small compared to the intramolecular Frenkel exciton. Therefore, the net transition dipole moment is largely determined by the intramolecular component resulting in a relatively small mutual difference between the polarization angles. Ultimately, the molecular alignment within the micro-textured crystallites can be deduced and, with that, the excited state transitions can be spotted., Comment: 12 pages, 8 figures

A titanocene‐catalyzed regiodivergent radical arylation is described that allows access to either enantiomerically pure tetrahydroquinolines or indolines from a common starting material. The regioselectivity of epoxide opening that results in the high selectivity of heterocycle formation is controlled by two factors, the absolute configuration of the enantiopure ligands of the (C5H4R)2TiX2 catalyst and the inorganic ligand X (X=Cl, OTs). The overall reaction is atom‐economical and constitutes a radical Friedel–Crafts alkylation., Indolines and tetrahydroquinolines are formed from the same substrates by titanocene catalysis. The absolute configuration of the cyclopentadienyl ligand and the inorganic ligand determine the regioselectivity of the ring opening and diastereoselectivity of tje radical arylation in the regiodivergent radical arylation of epoxides.

A combinatorial method was devised and applied for the design and identification of substrate-analogue inhibitors of therapeutically relevant serine proteases, such as thrombin and factor Xa. We conceptualized imino acid derived diketomorpholines as generally applicable key intermediates prepared through solid-phase synthesis and prone to be cleaved with primary amines in a traceless fashion. The approach led to a compound library whose members were prepared under bioassay-compatible conditions and directly subjected to the in situ evaluation, allowing a fast prediction of hit compounds. Highly active inhibitors for serine proteases of the coagulation cascade have been identified. The most potent dual inhibitor, 16K, has a binding affinity of 23.9 nM to thrombin and 32.8 nM to factor Xa.

A phosphanido-type bridged bis(imidazolium) salt, readily prepared in two steps via reductive deselenization of a tricyclic 1,4-diphosphinine diselone, affords access to a novel anionic P-functional tricyclic bis(NHC) via deprotonation. The former also offers a P-functionalization/deprotonation sequence to access the first mixed P-substituted tricyclic bis(NHCs), as well as coordination of the phosphorus centers to rhodium(I) fragments.

A new, mild and efficient protocol for the synthesis of trifluoromethyl-indolyl-phenylethanols by the reaction of indoles with a variety of aromatic fluoromethyl ketones in the presence of K2CO3 (15 mol%) and nBu4PBr (15 mol%) in water. The desired products were obtained in good to excellent yields without requiring the column chromatography purification. The reusability of the catalytic system and large-scale synthesis of indolyl-phenylethanols, which would further transform into biological active indole-derived compounds, are further advantages of this protocol.

Synthesis of the first tricyclic bis(carbenes) with facially opposed imidazole-2-ylidenes and two linking phosphorus centres in different oxidation states is presented using a modular, high-yield synthetic route. The formation of homo bimetallic coinage metal(i) complexes provides a first glimpse on their potential use.

The syntheses of a formazan and a verdazyl radical are reported along with their crystal structures, UV–Vis spectra, and the EPR spectrum of the radical. In addition, the isolation of a possible by-product was achieved., The title compounds, C19H15BrN4, C20H16BrN4 and C20H15BrN4, are nitro­gen-rich organic compounds that are related by their synthesis. The verdazyl radical, in which stacking leads to anti­ferromagnetic inter­actions, was reported previously [Iwase et al. (2013 ▸). Phys. Rev. B, 88, 184431]. For this compound, improved structural data and spectroscopic data are presented. The other two compounds have been crystallized for the first time and form stacks of dimers, roughly along the a-axis direction of the crystal. The formazan mol­ecule shows signs of rapid intra­molecular H-atom exchange typical for this class of compounds and spectroscopic data are provided in addition to the crystal structure. The triazole compound appears to be a side-product of the verdazyl synthesis.

A new bis(salicylimine) ligand based on the Tröger's base scaffold was synthesized in racemic and enantiomerically pure form. Upon coordination to zinc(II) ions this ligand undergoes highly diastereoselective self-assembly into neutral dinuclear double-stranded helicates as proven by XRD analysis and via comparison of experimental ECD spectra with those simulated with quantum-chemical methods. When the racemic ligand was used, self-assembly occurs under narcissistic self-sorting resulting in the formation of a racemic pair of helicates as revealed by NMR spectroscopy and XRD analysis.

Dibenzo[a,e]pentalene (DBP) is a low-bandgap organic semiconductor. A versatile synthetic route to DBPs substituted with aryl or alkyl groups in the 5,10-positions and electron-donating or -accepting functionalities in the 2,7-positions is described. Six donor- or acceptor-functionalized DBP derivatives were synthesized that show amphoteric redox behavior and band gaps around 2 eV. Through choice of the 2,7-substituents, the HOMO/LUMO energy levels and band gaps can be adjusted within a range of up to 0.6 eV. In the solid state, the DBP derivatives assume herringbone-type packing structures.

A systematic, efficient approach to first complexes containing a triple bond between niobium and the elements silicon, germanium or tin is reported. The approach involves a metathetical exchange of the niobium-centered nucleophile (NMe4)[Nb(CO)4(κ2-tmps)] (1) (tmps = MeSi(CH2PMe2)3) with a suitable organotetrel(II)halide. Compound 1 was obtained from (NMe4)[Nb(CO)6] and the triphosphane tmps by photodecarbonylation. Reaction of 1 with the disilene E-Tbb(Br)SiSi(Br)Tbb in the presence of 4-dimethylaminopyridine afforded selectively the red-brown silylidyne complex [(κ3-tmps)(CO)2NbSi–Tbb] (2-Si, Tbb = 4-tert-butyl-2,6-bis(bis(trimethylsilyl)methyl)phenyl). Similarly, treatment of 1 with E(ArMes)Cl (E = Ge, Sn; ArMes = 2,6-mesitylphenyl) afforded after elimination of (NMe4)Cl and two CO ligands the deep magenta colored germylidyne complex [(κ3-tmps)(CO)2NbGe–ArMes] (3-Ge), and the deep violet, light-sensitive stannylidyne complex [(κ3-tmps)(CO)2NbSn–ArMes] (3-Sn), respectively. Formation of 3-Sn proceeds via the niobiastannylene [(κ3-tmps)(CO)3Nb–SnArMes] (4-Sn), which was detected by IR and NMR spectroscopy. The niobium tetrylidyne complexes 2-Si, 3-Ge and 3-Sn were fully characterized and their solid-state structures determined by single-crystal X-ray diffraction studies. All complexes feature an almost linear tetrel coordination and the shortest Nb–E bond lengths (d(Nb–Si) = 232.7(2) pm; d(Nb–Ge) = 235.79(4) pm; d(Nb–Sn) = 253.3(1) pm) reported to date. Reaction of 3-Ge with a large excess of H2O afforded upon cleavage of the Nb–Ge triple bond the hydridogermanediol Ge(ArMes)H(OH)2. Photodecarbonylation of [CpNb(CO)4] (Cp = η5-C5H5) in the presence of Ge(ArMes)Cl afforded the red-orange chlorogermylidene complex [Cp(CO)3NbGe(ArMes)Cl] (5-Ge). The molecular structure of 5-Ge features an upright conformation of the germylidene ligand, a trigonal–planar coordinated Ge atom, and a Nb–Ge double bond length of 251.78(6) pm, which lies in-between the Nb–Ge triple bond length of 3-Ge (235.79(4) pm) and a Nb–Ge single bond length (267.3 pm). Cyclic voltammetric studies of 2-Si, 3-Ge, and 3-Sn reveal several electron-transfer steps. One-electron oxidation and reduction of the germylidyne complex of 3-Ge in THF are electrochemically reversible suggesting that both the radical cation and radical anion of 3-Ge are accessible species in solution.

8-Arylethynylxanthine derivatives are potent, selective adenosine A2A receptor antagonists, which represent (potential) therapeutics for Parkinson&rsquo, s disease, Alzheimer&rsquo, s dementia, and the immunotherapy of cancer. 6-Amino-5-amidouracil derivatives are important precursors for the synthesis of such xanthines. We noticed an unexpected duplication of NMR signals in many of these uracil derivatives. Here, we present a detailed analytical study of structurally diverse 6-amino-5-carboxamidouracils employing dynamic and two-dimensional NMR spectroscopy, density functional theory calculations, and X-ray analysis to explain the unexpected properties of these valuable drug intermediates.

The 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivative BIM-46174 has received attention as Gα(q) inhibitor. We conducted structural reductions to monocyclic and bicyclic substructures to explore the chemical space of BIM fragments and to gain insights into the pharmacophore of BIM-type Gα(q) inhibitors. Two piperazin-2-one-containing fragments and a small library of bicyclic lactams featuring fused pyrazine and diazepine rings were synthesized and evaluated. The results of a second messenger-based cellular assay indicate that the entire BIM structure is required for efficient Gα(q) inhibition.

Substituted xanthine derivatives are important bioactive molecules. Herein we report on a new, practical synthesis of 6-amino-5-carboxamidouracils, the main building blocks for the preparation of 8-substituted xanthines, by condensation of 5,6-diaminouracil derivatives and various carboxylic acids using the recently developed non-hazardous coupling reagent COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate). Optimized reaction conditions led to the precipitation of pure products after only 5 to 10 min of reaction time. The method tolerates a variety of substituted 5,6-diaminouracil and carboxylic acid derivatives as starting compounds resulting in most cases in more than 80% isolated yield. Regioselectivity of the reaction yielding only the 5-carboxamido-, but not the 6-carboxamidouracil derivatives, was unambiguously confirmed by single X-ray crystallography and multidimensional NMR experiments. The described method represents a convenient, fast access to direct precursors of 8-substituted xanthines under mild conditions without the necessity of hazardous coupling or chlorinating reagents.