Glycosylation spectral signatures for glioma grade discrimination using Raman spectroscopy.

BACKGROUND: Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific glioma biomarkers that would aid tumour subtyping and minimally invasive early diagnosis. Aberrant glycosylation is an important post-translational modification in cancer and is implicated in glioma progression. Raman spectroscopy (RS), a vibrational spectroscopic label-free technique, has already shown promise in cancer diagnostics. METHODS: RS was combined with machine learning to discriminate glioma grades. Raman spectral signatures of glycosylation patterns were used in serum samples and fixed tissue biopsy samples, as well as in single cells and spheroids. RESULTS: Glioma grades in fixed tissue patient samples and serum were discriminated with high accuracy. Discrimination between higher malignant glioma grades (III and IV) was achieved with high accuracy in tissue, serum, and cellular models using single cells and spheroids. Biomolecular changes were assigned to alterations in glycosylation corroborated by analysing glycan standards and other changes such as carotenoid antioxidant content. CONCLUSION: RS combined with machine learning could pave the way for more objective and less invasive grading of glioma patients, serving as a useful tool to facilitate glioma diagnosis and delineate biomolecular glioma progression changes.

Borane Adducts of Aromatic Phosphorus Heterocycles: Synthesis, Crystallographic Characterization and Reactivity of a Phosphinine-B(C6 F5 )3 Lewis Pair.

A phosphinine-borane adduct of a Me3 Si-functionalized phosphinine and the Lewis acid B(C6 F5 )3 has been synthesized and characterized crystallographically for the first time. The reaction strongly depends on the nature of the substituents in the α-position of the phosphorus heterocycle. In contrast, the reaction of B2 H6 with various substituted phosphinines leads to an equilibrium between the starting materials and the phosphinine-borane adducts that is determined by the Lewis basicity of the phosphinine. The novel phosphinine borane adduct (6-B(C6 F5 )3 ) shows rapid and facile insertion and [4+2] cycloaddition reactivity towards phenylacetylene. A hitherto unknown dihydro-1-phosphabarrelene is formed with styrene. The reaction with an ester provides a new, facile and selective route to 1-R-phosphininium salts. These salts then undergo a [4+2] cycloaddition in the presence of Me3 Si-C≡CH and styrene to cleanly form unprecedented derivatives of 1-R-phosphabarrelenium salts.

Phospholenes from Phosphabenzenes by Selective Ring Contraction.

A 3-amino-functionalized phosphabenzene (phosphinine) has been synthesized and structurally characterized. The pyramidalized nitrogen atom of the dimethylamino substituent indicates only a weak interaction between the lone pair of the nitrogen atom and the aromatic phosphorus heterocycle, resulting in somewhat basic character. It turned out that the amino group can indeed be protonated by HCl. In contrast to pyridines, however, the phosphabenzene-ammonium salt undergoes a selective ring contraction to form a hydroxylphospholene oxide in the presence of additional water. Based on deuterium labeling experiments and quantum chemical calculations, a rational mechanism for this hitherto unknown conversion is proposed.

Reactivity of Sodium Pentaphospholide Na[cyclo-P5 ] towards C≡E (E=C, N, P) Triple Bonds.

A diglyme solution of Na[cyclo-P5 ] (1) reacts with alkynes and isolobal nitriles and phosphaalkynes to afford the otherwise elusive (aza)phospholide anions 2 a-c, 4 a,b, and 6. The reaction of Na[cyclo-P5 ] with alkynes and nitriles was studied by means of DFT methods, which suggested a concerted mechanism for the formation of 2 a and 4 b. The anions 2 a-c, 4 a,b, and 6 coordinate in an η5 -fashion towards FeII to give the sandwich (aza)phosphametallocenes 3 a-c, 5 a,b and 7 in moderate to good yields. The new compounds were characterized by means of multinuclear NMR spectroscopy, single-crystal X-ray diffraction and cyclic voltammetry.

Photochemical C(sp)-C(sp2) Bond Activation in Phosphaalkynes: A New Route to Reactive Terminal Cyaphido Complexes LnM-C≡P.

The photochemical activation of the C(sp)-C(sp2) bond in Pt(0)-η2-aryl-phosphaalkyne complexes leads selectively to coordination compounds of the type LnPt(aryl)(C≡P). The oxidative addition reaction is a novel, clean, and atom-economic route for the synthesis of reactive terminal Pt(II)-cyaphido complexes, which can undergo [3 + 2] cycloaddition reactions with organic azides, yielding the corresponding Pt(II)-triazaphospholato complexes. The C-C bond cleavage reaction is thermodynamically uphill. Upon heating, the reverse and quantitative reductive elimination toward the Pt(0)-phosphaalkyne-π-complex is observed.

Making Aromatic Phosphorus Heterocycles More Basic and Nucleophilic: Synthesis, Characterization and Reactivity of the First Phosphinine Selenide.

The synthesis and isolation of a phosphinine selenide was achieved for the first time by reacting red selenium with 2,6-bis(trimethylsilyl)phosphinine. The rather large coupling constant of 1 JP,Se =883 Hz is in line with a P-Se bond of high s-character. The σ-electron donating Me3 Si-substituents significantly increase the energy of the phosphorus lone pair and hence its basicity, making the heterocycle considerably more basic and nucleophilic than the unsubstituted phosphinine C5 H5 P, as confirmed by the calculated gas phase basicities. NBO calculations further reveal that the lone pairs of the selenium atom are stabilized through donor-acceptor interactions with antibonding orbitals of the aromatic ring. The novel phosphinine selenide shows a distinct reactivity towards hexafluoro-2-butyne, Au(I)Cl as well as i PrOH. Our results pave the way for new perspectives in the chemistry of phosphorus in low coordination.

Room Temperature Iron-Catalyzed Transfer Hydrogenation and Regioselective Deuteration of Carbon-Carbon Double Bonds.

An iron catalyst has been developed for the transfer hydrogenation of carbon-carbon multiple bonds. Using a well-defined ß-diketiminate iron(II) precatalyst, a sacrificial amine and a borane, even simple, unactivated alkenes such as 1-hexene undergo hydrogenation within 1 h at room temperature. Tuning the reagent stoichiometry allows for semi- and complete hydrogenation of terminal alkynes. It is also possible to hydrogenate aminoalkenes and aminoalkynes without poisoning the catalyst through competitive amine ligation. Furthermore, by exploiting the separate protic and hydridic nature of the reagents, it is possible to regioselectively prepare monoisotopically labeled products. DFT calculations define a mechanism for the transfer hydrogenation of propene with nBuNH2 and HBpin that involves the initial formation of an iron(II)-hydride active species, 1,2-insertion of propene, and rate-limiting protonolysis of the resultant alkyl by the amine N-H bond. This mechanism is fully consistent with the selective deuteration studies, although the calculations also highlight alkene hydroboration and amine-borane dehydrocoupling as competitive processes. This was resolved by reassessing the nature of the active transfer hydrogenation agent: experimentally, a gel is observed in catalysis, and calculations suggest this can be formulated as an oligomeric species comprising H-bonded amine-borane adducts. Gel formation serves to reduce the effective concentrations of free HBpin and nBuNH2 and so disfavors both hydroboration and dehydrocoupling while allowing alkene migratory insertion (and hence transfer hydrogenation) to dominate.

Iron Catalyzed Dehydrocoupling of Amine- and Phosphine-Boranes.

Catalytic dehydrocoupling methodologies, whereby dihydrogen is released from a substrate (or intermolecularly from two substrates) is a mild and efficient method to construct main group element-main group element bonds, the products of which can be used in advanced materials, and also for the development of hydrogen storage materials. With growing interest in the potential of compounds such as ammonia-borane to act as hydrogen storage materials which contain a high weight% of H2, along with the current heightened interest in base metal catalyzed processes, this review covers recent developments in amine and phosphine dehydrocoupling catalyzed by iron complexes. The complexes employed, products formed and mechanistic proposals will be discussed.

Advancing Brain Research through Surface-Enhanced Raman Spectroscopy (SERS): Current Applications and Future Prospects.

Surface-enhanced Raman spectroscopy (SERS) has recently emerged as a potent analytical technique with significant potential in the field of brain research. This review explores the applications and innovations of SERS in understanding the pathophysiological basis and diagnosis of brain disorders. SERS holds significant advantages over conventional Raman spectroscopy, particularly in terms of sensitivity and stability. The integration of label-free SERS presents promising opportunities for the rapid, reliable, and non-invasive diagnosis of brain-associated diseases, particularly when combined with advanced computational methods such as machine learning. SERS has potential to deepen our understanding of brain diseases, enhancing diagnosis, monitoring, and therapeutic interventions. Such advancements could significantly enhance the accuracy of clinical diagnosis and further our understanding of brain-related processes and diseases. This review assesses the utility of SERS in diagnosing and understanding the pathophysiological basis of brain disorders such as Alzheimer's and Parkinson's diseases, stroke, and brain cancer. Recent technological advances in SERS instrumentation and techniques are discussed, including innovations in nanoparticle design, substrate materials, and imaging technologies. We also explore prospects and emerging trends, offering insights into new technologies, while also addressing various challenges and limitations associated with SERS in brain research.

Uncovering potential diagnostic and pathophysiological roles of α-synuclein and DJ-1 in melanoma.

BACKGROUND: Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma. METHODS: The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein-protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in vitro cellular models and ELISA immunoassays. RESULTS: α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cells induced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability. CONCLUSION: α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.

Mechanistic investigations of the Fe(ii) mediated synthesis of squaraines.

The scission and homologation of CO is a fundamental process in the Fischer-Tropsch reaction. However, given the heterogeneous nature of the catalyst and forcing reaction conditions, it is difficult to determine the intermediates of this reaction. Here we report detailed mechanistic insight into the scission/homologation of CO by two-coordinate iron terphenyl complexes. Mechanistic investigations, conducted using in situ monitoring and reaction sampling techniques (IR, NMR, EPR and Mössbauer spectroscopy) and structural characterisation of isolable species, identify a number of proposed intermediates. Crystallographic and IR spectroscopic data reveal a series of migratory insertion reactions from 1Mes to 4Mes. Further studies past the formation of 4Mes suggest that ketene complexes are formed en route to squaraine 2Mes and iron carboxylate 3Mes, with a number of ketene containing structures being isolated, in addition to the formation of unbound, protonated ketene (8). The synthetic and mechanistic studies are supported by DFT calculations.

Highly selective, reversible water activation by P,N-cooperativity in pyridyl-functionalized phosphinines.

Tetrapyridyl-functionalized phosphinines were prepared and structurally characterized. The donor-functionalized aromatic phosphorus heterocycles react highly selectively and even reversibly with water. Calculations reveal P,N-cooperativity for this process, with the flanking pyridyl groups serving to kinetically enhance the formal oxidative addition process of H2O to the low-coordinate phosphorus atom via H-bonding. Subsequent tautomerization forms 1,2-dihydrophosphinine derivatives, which can be quantitatively converted back to the phosphinine by applying vacuum, even at room temperature. This process can be repeated numerous times, without any sign of decomposition of the phosphinine. In the presence of CuI·SMe2, dimeric species of the type ([Cu2I2(phosphinine)]2) are formed, in which each phosphorus atom shows the less common µ2-bridging 2e--lone-pair-donation to two Cu(i)-centres. Our results demonstrate that fully unsaturated phosphorus heterocycles, containing reactive P[double bond, length as m-dash]C double bonds, are interesting candidates for the activation of E-H bonds, while the aromaticity of such compounds plays an appreciable role in the reversibility of the reaction, supported by NICS calculations.

Phosphinine Selenide: Noncovalent Interactions with Organoiodines and Elemental Iodine, and Reactivity towards Potassium Cyanide.

A co-crystalline adduct consisting of a phosphinine selenide and an organohalide was obtained by slow evaporation of the solvent from a mixture of 2,6-bis(trimethylsilyl)phosphinine selenide and 1,4-diiodotetrafluorobenzene (1,4-TFDIB). The crystallographic characterization of the product shows π-π stacking, F⋅⋅⋅H hydrogen bonding between 1,4-TFDIB and the phosphinine selenide, as well as F⋅⋅⋅F interactions between 1,4-TFDIB molecules. Moreover, the phosphorus heterocycle could be crystallized with diiodine to form a 1 : 1 adduct. The d(I-I) distance in this compound is 2.8475(3) Å, which is shorter than the corresponding one in triphenylphosphine selenide diiodide, reflecting the weaker net-donor power of the phosphinine selenide towards diiodine. The phosphinine selenide could also be used as a selenium transfer reagent to generate KSeCN from KCN.

Phosphinine Selenide: Noncovalent Interactions with Organoiodines and Elemental Iodine, and Reactivity towards Potassium Cyanide.

Invited for this month's cover is the group of Prof. Dr. Christian Müller from Freie Universität Berlin, Germany. The cover picture shows a phosphinine selenide that interacts with organoiodines and halogens to form co-crystalline and charge-transfer adducts. More information can be found in the Research Article by Christian Müller and co-workers.

Homotropic Cooperativity in Iron-Catalyzed Alkyne Cyclotrimerizations.

Enhancing catalytic activity through synergic effects is a current challenge in homogeneous catalysis. In addition to the well-established metal-metal and metal-ligand cooperation, we showcase here an example of self-activation by the substrate in controlling the catalytic activity of the two-coordinate iron complex [Fe(2,6-Xyl2C6H3)2] (1, Xyl = 2,6-Me2C6H3). This behavior was observed for aryl acetylenes in their regioselective cyclotrimerization to 1,2,4-(aryl)-benzenes. Two kinetically distinct regimes are observed dependent upon the substrate-to-catalyst ratio ([RC≡CH]0/[1]0), referred to as the low ([RC≡CH]0/[1]0 < 40) and high ([RC≡CH]0/[1]0 > 40) regimes. Both showed sigmoidal kinetic response, with positive Hill indices of 1.85 and 3.62, respectively, and nonlinear Lineweaver-Burk replots with an upward curvature, which supports positive substrate cooperativity. Moreover, two alkyne molecules participate in the low regime, whereas up to four are involved in the high regime. The second-order rate dependence on 1 indicates that binuclear complexes are the catalytically competent species in both regimes, with that in the high one being 6 times faster than that involved in the low one. Moreover, Eyring plot analyses revealed two different catalytic cycles, with a rate-determining step more endergonic in the low regime than in the high one, but with a more ordered transition state in the high regime than in the low one.

Phosphorus derivatives of mesoionic carbenes: synthesis and characterization of triazaphosphole-5-ylidene → BF3 adducts.

Trimethylsilyl-substituted triazaphospholes were synthesized by a [3+2] cycloaddition reaction between organic azides and (CH3)3Si-CP. In an attempt to isolate their N-alkylated products, the formation of BF3 adducts of unprecedented triazaphosphol-5-ylidenes was found. The nature of the carboncarbene-boron bond was investigated within the DFT framework, revealing a strong donation of electrons from the carbene carbon atom to the boron atom combined with weak back-bonding.

Highly flexible phosphabenzenes: a missing coordination mode of 2,4,6-triaryl-λ3-phosphinines.

The reaction of 2,4,6-triaryl-λ3-phosphinine-Cr(CO)3-π-complexes with [Rh(COD)2]BF4 leads to unusual diamagnetic Rh0-dimers, which contain two phosphinine-π-complexes acting as a bridging 2e--ligand towards the Rh2(CO)2 core. These compounds represent a missing coordination mode for the aromatic 6-membered phosphorus heterocycle.

Triple dehydrofluorination as a route to amidine-functionalized, aromatic phosphorus heterocycles.

An unexpected route to hitherto unknown amidine-functionalized phosphinines has been developed that is rapid and simple. Starting from primary amines and CF3-substituted λ3,σ2-phosphinines, a cascade of dehydrofluorination reactions leads selectively to ortho-amidinephosphinines. DFT calculations reveal that this unusual transformation can take place via a series of nucleophilic attacks at the electrophilic, low-coordinate phosphorus atom.

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients.

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan-Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the 'MUC4/MMP9/EGFR axis' may play a vital role in glioblastoma diagnostics.

One-step methylation of aromatic phosphorus heterocycles: synthesis and crystallographic characterization of a 1-methyl-phosphininium salt.

For the first time, the direct synthesis of 1-methyl-phosphininium salts has been achieved by reacting aromatic λ3,σ2-phosphinines with the readily available dimethyl chloronium salt [(CH3)2Cl]+[Al(OTeF5)4]-. The remarkably high electrophilicity of the alkylation reagent in combination with the weakly coordinating pentafluoro-orthotelluratoaluminate anion offers excellent conditions for this one-step approach. Our simple and quantitative access to 1-methyl-phosphininium salts will pave the way to explore the chemistry of such reactive species in more detail.