Spin–Orbit Charge-Transfer Intersystem Crossing (ISC) in Compact Electron Donor–Acceptor Dyads: ISC Mechanism and Application as Novel and Potent Photodynamic Therapy Reagents

Spin–orbit charge-transfer intersystem crossing (SOCT-ISC) is useful for the preparation of heavy atom-free triplet photosensitisers (PSs). Herein, a series of perylene-Bodipy compact electron donor/acceptor dyads showing efficient SOCT-ISC is prepared. The photophysical properties of the dyads were studied with steady-state and time-resolved spectroscopies. Efficient triplet state formation (quantum yield Φ_T=60 %) was observed, with a triplet state lifetime (τ_T=436 μs) much longer than that accessed with the conventional heavy atom effect (τ_T=62 μs). The SOCT-ISC mechanism was unambiguously confirmed by direct excitation of the charge transfer (CT) absorption band by using nanosecond transient absorption spectroscopy and time-resolved electron paramagnetic resonance (TREPR) spectroscopy. The factors affecting the SOCT-ISC efficiency include the geometry, the potential energy surface of the torsion, the spin density for the atoms of the linker, solvent polarity, and the energy matching of the ¹CT/³LE states. Remarkably, these heavy atom-free triplet PSs were demonstrated as a new type of efficient photodynamic therapy (PDT) reagents (phototoxicity, EC₅₀=75 nm ), with a negligible dark toxicity (EC₅₀=78.1 μm ) compared with the conventional heavy atom PSs (dark toxicity, EC₅₀=6.0 μm, light toxicity, EC₅₀=4.0 nm ). This study provides in-depth understanding of the SOCT-ISC, unveils the design principles of triplet PSs based on SOCT-ISC, and underlines their application as a new generation of potent PDT reagents.     

Electrophilicity Scale of Activated Amides: 17O NMR and 15N NMR Chemical Shifts of Acyclic Twisted Amides in N−C(O) Cross-Coupling

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to n_N→π*_C=O conjugation. In this study, we report electrophilicity scale by exploiting ¹⁷O NMR and ¹⁵N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.     

Reversible Activation of Water by an Air- and Moisture-Stable Frustrated Rhodium Nitrogen Lewis Pair

[Cp*Rh(κ³N,N′,P- L )][SbF₆] (Cp*=C₅Me₅), bearing a guanidine-derived phosphano ligand L , behaves as a “dormant” frustrated Lewis pair and activates H₂ and H₂O in a reversible manner. When D₂O is employed, a facile H/D exchange at the Cp* ring takes place through sequential C(sp³)−H bond activation.     

Two Types of σ-Allenyl Complexes from Reactions of Silylenes and Germylenes with Chromium Fischer Alkynyl(alkoxy)carbenes

The reactivity of amidinatotetrylenes of the type E(tBu₂bzm)R¹ (E=Si, Ge; tBu₂bzm=N,N′-bis(tertbutyl)benzamidinate; R¹=alkyl or aryl) with the chromium Fischer alkynylcarbene complexes [Cr{C(OEt)C₂R²}(CO)₅] (R²=Ph; ferrocenyl, Fc) has been studied. At room temperature, two different reaction pathways have been identified: (a) attack of the amidinatotetrylene to the alkynyl C² atom (γ-attack), which leads to σ-allenyl complexes in which the original C_carbene atom maintains its attachment to the Cr(CO)₅ and OEt groups (compounds 3 ), and (b) attack of the amidinatotetrylene to the C_carbene atom (α-attack), which ends in σ-allenyl complexes in which the original C_carbene atom is not attached to the metal atom and has been inserted into an E−N bond of the amidinatotetrylene forming an E-C-N-C-N five-membered ring (compounds 4 ). It has been found that compounds 3 are thermodynamically less stable than their corresponding 4 isomers and that some of the former (E=Ge; R¹=CH₂SiMe₃) can be transformed into the latter upon heating. At high temperatures (>70 °C) the reactions involving bulky amidinatotetrylenes (R¹=Mes, tBu) end in the carbene-substitution products [Cr{E(tBu₂bzm)R¹}(CO)₅].     

Engineering Multifunctional Gold Decorated Dendritic Mesoporous Silica/Tantalum Oxide Nanoparticles for Intraperitoneal Tumor‐Specific Delivery

Nonspecific high‐energy radiation for treatment of metastatic ovarian cancer is limited by damage to healthy organs, which can be mitigated by the use of radiosensitizers and image‐guided radiotherapy. Gold (Au) and tantalum oxide (TaO_x) nanoparticles (NPs), by virtue of their high atomic numbers, find utility in the design of bimetallic NP systems capable of high‐contrast computed tomography (CT) imaging as well as a potential radiosensitizing effect. These two radio‐dense metals are integrated into dendritic mesoporous silica NPs (dMSNs) with radial porous channels for high surface‐area loading of therapeutic agents. This approach results in stable, monodispersed dMSNs with a uniform distribution of Au on the surface and TaO_x in the core that exhibits CT attenuation up to seven times greater than iodine or monometallic dMSNs without either TaO_x or Au. Tumor targeting is assessed in a metastatic ovarian cancer mouse model. Ex vivo micro‐CT imaging of collected tumors shows that these NPs not only accumulate at tumor sites but also penetrate inside tumor tissues. This study demonstrates that after intraperitoneal administration, rationally designed bimetallic NPs can simultaneously serve as targeted contrast agents for imaging tumors and to enhance radiation therapy in metastatic ovarian cancer.     

The development and validation of a novel LC–MS/MS method for the quantification of cenicriviroc in human plasma and cerebrospinal fluid

A high-performance liquid chromatography tandem mass spectrometric method was developed and validated for cenicriviroc (CVC) quantification in human plasma and cerebrospinal fluid (CSF). The method involved precipitation with acetonitrile and injecting supernatants onto the column. Separation was achieved on an XBridge C₁₈ column with a gradient elution of 0.1% formic acid in water and acetonitrile. Analyte detection was conducted in positive ion mode using selected reaction monitoring. The m/z transitions were: CVC (697.3 → 574.3) and CVC-d7 (704.4 → 574.3). Calibration curve ranged from 5 to 1000 ng/mL for plasma and from 0.241 to 15.0 ng/mL for CSF. The intra- and inter-day precision and accuracy were <15% for both plasma and CSF across four different concentrations. CVC recovery from plasma and artificial CSF was >90%. The method was utilized for the measurement of patients’ plasma and CSF samples taking a dose of 50, 150 and 300 mg q.d.     

High Activity and Selective Fischer–Tropsch Catalysts for Use in a Microchannel Reactor

Each process configuration for practicing the Fischer–Tropsch synthesis places demands particular to that configuration on the catalyst to be used. We discuss how a particular catalyst, prepared by the OMX (organic matrix combustion) method, when used in conjunction with the Velocys microchannel reactor system, results in a very stable, high performance Fischer–Tropsch synthesis system. With the ability to remove heat far more effectively than a conventional reactor system, this microchannel reactor requires a catalyst with much higher volumetric reactive site density. Further, with such a high volumetric reaction rate, mass transfer effects will be important in both the observed activity and selectivity of the operating catalyst. Nevertheless, the catalyst prepared using the OMX method exhibits an apparent turnover frequency which is considerably higher than reported for other catalysts in the literature. In addition to high activity, an economically useful catalyst must exhibit a stable, high selectivity for liquid products and be able to recover near-fresh performance using a regeneration approach which can be carried out with the catalyst in-place. An example of such a stable, multiply regenerated catalyst is given. Finally, further development has focused on a catalyst with even higher C₅₊ selectivity.     

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala and Phe–Lys peptide sequences) were synthesized by conjugation of the α_vβ₃‐integrin ligand cyclo[DKP–RGD]‐CH₂NH₂ ( 2 ) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker ( 8 ) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified α_Vβ₃‐integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8 , which possesses a nonpeptide “uncleavable” linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF‐CEM (α_Vβ₃?) and its subclone CCRF‐CEM α_Vβ₃ (α_Vβ₃+). Fairly effective integrin targeting was displayed by the cyclo[DKP–RGD]–Val–Ala–PTX conjugate ( 6 ), which was found to differentially inhibit proliferation in antigen‐positive CCRF‐CEM α_Vβ₃ versus antigen‐negative isogenic CCRF‐CEM cells. The total lack of activity displayed by the “uncleavable” cyclo[DKP–RGD]–PTX conjugate ( 8 ) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.     

Electrochemical Sensing of Uric Acid Using Glassy Carbon Modified with Multiwall Carbon Nanotubes Dispersed in Polyethylenimine

This work reports the advantages of using glassy carbon electrodes modified with multiwall carbon nanotubes (MWCNT) dispersed in polyethylenimine (PEI). The presence of MWCNTs wrapped by PEI largely facilitated the strong adsorption of uric acid (UA) and allowed its highly sensitive and selective quantification even in the presence of high excess of ascorbic acid. The selected conditions for the electrochemical sensing were 5 s accumulation at ?0.300 V under stirring and quantification in a 0.050 M phosphate buffer solution pH 7.40 by differential pulse voltammetry adsorptive‐stripping after medium exchange. The platform allowed the successful application in the quantification of UA in urine.     

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.