Photochemical Targeting of Mitochondria to Overcome Chemoresistance in Ovarian Cancer †

Ovarian cancer is the most lethal gynecologic malignancy with a stubborn mortality rate of ~65%. The persistent failure of multiline chemotherapy, and significant tumor heterogeneity, has made it challenging to improve outcomes. A target of increasing interest is the mitochondrion because of its essential role in critical cellular functions, and the significance of metabolic adaptation in chemoresistance. This review describes mitochondrial processes, including metabolic reprogramming, mitochondrial transfer and mitochondrial dynamics in ovarian cancer progression and chemoresistance. The effect of malignant ascites, or excess peritoneal fluid, on mitochondrial function is discussed. The role of photodynamic therapy (PDT) in overcoming mitochondria-mediated resistance is presented. PDT, a photochemistry-based modality, involves the light-based activation of a photosensitizer leading to the production of short-lived reactive molecular species and spatiotemporally confined photodamage to nearby organelles and biological targets. The consequential effects range from subcytotoxic priming of target cells for increased sensitivity to subsequent treatments, such as chemotherapy, to direct cell killing. This review discusses how PDT-based approaches can address key limitations of current treatments. Specifically, an overview of the mechanisms by which PDT alters mitochondrial function, and a summary of preclinical advancements and clinical PDT experience in ovarian cancer are provided.     

Concerning the Absorption and Photochemical Properties of an ω-4-Dimethylaminobenzal Hypericin Derivative

 A hypericin derivative containing ω,ω ′-4-dimethylaminobenzal residues was shown to undergo an intramolecular [2 + 2] cycloaddition upon irradiation leading to a cyclobutane derivative whose main absorption band is hardly shifted as compared to hypericin. The corresponding ω-substituted derivative displayed a 34 nm bathochromic shift and a strongly reduced fluorescence quantum yield rendering it a nice candidate for a photodynamic therapy agent. Unfortunately, however, it produced virtually no photosensitized active oxygen species, making it thus unsuited for this purpose.     

Nanocaging Rose Bengal to Inhibit Aggregation and Enhance Photo-induced Oxygen Consumption†

Photosensitized crosslinking of proteins in tissues has many medical applications including sealing wounds, strengthening tissues, and beneficially altering tissue properties. Rose Bengal (RB) is used most frequently as the photosensitizer but is not as efficient as would be desired for broad utilization in medicine. Aggregation of RB, at the high concentrations used for medical treatments, decreases the yield of singlet oxygen, which mediates protein crosslinking. We hypothesized that nanocages that sequester RB would inhibit self-association, increasing photosensitization efficiency. We tested cucurbituril and cyclodextrin nanocages, demonstrating that hydroxypropyl-functionalized cyclodextrins are most effective in inhibiting RB aggregation. For these RB/cyclodextrin solutions, we investigated the effect of nanocaging on the photobleaching and oxygen consumption kinetics under 530 nm LED light in aqueous phosphate-buffered solutions. At 100 μm RB, the initial oxygen consumption rates increased by 58% and 80% compared with uncaged RB for the β and γ (2-hydroxypropyl) cyclodextrins, respectively. For 1 mm RB, the enhancement in these rates was much greater, about 200% and 300%, respectively. In addition, at 1 mm RB these two cyclodextrins increased the RB photobleaching rate by ~20% and ~75%. These results suggest that nanocages can minimize RB aggregation and may lead to higher-efficiency photo-medical therapies.     

Unraveling the Photophysical Characteristics,Aromaticity, and Stability of π–Extended Acene-Quinodimethyl Thioamides†

Poly-aromatic systems that contain quinodimethyl (QDM) units are appealing for several photonic and spintronic applications owing to the unique electronic structure, aromaticity, and spin state(s) of the QDM ring. Herein, we report the synthesis and characterization of novel QDM-based chromophores 1 – 3 , which exhibit unique photo-excited behavior and aromaticity. Extending the aromatic core with a biphenyl/phenanthryl- and a pyrrolo-fragment led to reducing the optoelectronic bandgap and modulating the photophysics QDM 1 – 3 . Yet, QDM 2 and 3 suffer from “aromaticity imbalance” and become relatively unstable compared to the parent compound QDM 1 . Further assessment of local aromaticity using computational tools revealed that the pseudo-quinoidal ring B is the main driving force allowing to easily populate the excited triplet state of these chromophores. The present study provides complementary guidelines for designing novel non-classical poly-aromatic systems.     

Exploring the Antibacterial Properties of Lignin-coated Magnetic Nanoparticles Synthesized in a One-pot Process†

Given the current grave problems with antibiotic resistance, the discovery of novel, unconventional antibacterial drugs is not just important but also urgent. In this contribution, we report on the synthesis and testing of several composite nanomaterials that may find applications as therapeutic drugs or surface disinfectants. These materials are based on magnetic nanostructures coated with lignin, for example, lignin@FeCo. The magnetic properties of these nanocomposites facilitate removal or localization, whereas the lignin shell provides biocompatibility. These nanomaterials are mild antibacterials in the absence of light, but when illuminated become powerful antibacterial agents with typically ≥6 log units of bacterial reduction in 1–5 min of irradiation. These materials are strongly absorbing, including in the very useful NIR biological window, which we illustrate using 810 nm LED irradiation. We also show that in the short time required for antibacterial action, thermal changes are very small (≤5°C). Further, biocompatibility tests using fibroblasts show very limited cell damage and no enhanced adverse effect during 810 nm NIR illumination. As a surface coating for the active material, lignin provides a “trojan horse” strategy to facilitate the antibacterial action.     

Effect of Host Substitution on Photochemical Properties of Pyrene/β-Cyclodextrin Solid Complexes

Pyrene/β-cyclodextrin solid complexes (prepared using β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and 2,3,6-triacetyl-β-cyclodextrin as hosts) were characterized by means of fluorescence spectroscopy and time-resolved diffuse reflectance laser flash photolysis. The relative intensity of the 0–0 and 0–2 vibronic bands in the emission spectrum of pyrene is found to increase as substitution of the cyclodextrin hydroxyl groups increases. Furthermore, a concomitant shortening in pyrene triplet lifetime results. Interestingly, a significant decrease in pyrene radical anion yield and lifetime is observed with 2,3,6-triacetyl-β-cyclodextrin as host; this effect is ascribed to the potential ability of the host matrix to trap electrons.     

Photochemical addition of methanol to V60:Formation of 1,4-dimethoxyfullerene

The addition of methanol to C60 in the presence of acetylglycine (AG) was carried out under irradiation.The novel compound,1,4-dimethoxyl-l,4-dihydrofullerene (1),was isolated and characterized by FTIR,UV-vis,1H and 13C NMR,and FDMS.     

Are the Fluorescent Properties of the Cyan Fluorescent Protein Sensitive to Conditions of Oxidative Stress?

The modifications induced by reactive oxygen species (ROS) on fluorescent proteins (FPs) may have important implications for live cell fluorescence imaging. Using quantitative γ-radiolysis, we have studied the ROS-induced biochemical and photophysical perturbations on recombinant cyan fluorescent protein (CFP). After oxidation by the ˙OH radical, the protein displays a modified RP-HPLC elution profile, while the CFP fluorescence undergoes pronounced decreases in intensity and lifetime, without changes in its excitation and emission spectra. Meanwhile, the Förster resonant energy transfer (FRET) between the single W⁵⁷ and the chromophore remains unperturbed. These results rule out a direct oxidation of the CFP chromophore and of W⁵⁷ as well as major changes in the protein 3D structure, but show that new fluorescent forms associated to a higher level of dynamic quenching have been generated. Thus, strict in situ controls are required when CFP is to be used for FRET studies in situations of oxidative activity, or under strong illumination.     

Syntheses,Crystal Structures,and Properties of Ferrocene–Carboxylate Coordination Complexes Through Modulating the Auxiliary Ligands

Russian Journal of Coordination Chemistry - Self-assemblies of the flexible ferrocenyl block (3-carboxy-1-oxopropyl)-ferrocene with Zn(II)/Cd(II) cations in the presence of different N-containing...     

Redesign the α/β Fold to Enhance the Stability of Mannanase Man23 from <Emphasis Type="Italic">Bacillus subtilis</Emphasis>

In this work, we engineered the α/β fold of mannanase Man23 based on its molecular structure analysis to obtain more stable variants. By introducing 31 single-site mutations in the α/β fold and shuffling them, the incorporation of four mutations (K178R, K207R, N340R, and S354R) displayed a good balance between high activity and stability at higher temperature and broader pH. This quartet variant was characterized by an almost threefold increased activity and a sevenfold increased stability compared to native mannanase Man23. Our results suggest that such work is safe to increase our target protein stability with no loss of activity.     

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre-association (non-covalent ligand-protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed.     

Stability and Luminescence Properties of Tb (Ⅲ) Complexes with Adrenaline

Theinteractionofrareearthwithhormoneshouldbestudiedindetailinordertoexploremechanismoftheneuralandendocrineeffectofrareearth.Asacontinuationofourresearchontheinteractionofrareeafthwithhormone',stabilityandluminescencepropertiesofTb(lII)complexeswithadrenalineorepinephrine(3,4-dihydroxy-a(methylaminomethyl)benzylalcohol,(HO)zCeH3CH(OH)CH=NHCHshavebeenstudiedinthiswork.Satisfactoryresultshavebeenobtained.PotentiometrictitrationsweremadeonapHS-3CpHmeterbymeansofthemethoddescribedinpreviou…     

Synthesis,Electronic Properties and OLED Devices of Chromophores Based on λ5-Phosphinines

A new series of 2,4,6-triaryl-λ⁵-phosphinines have been synthesized that contain different substituents both on the carbon backbone and the phosphorus atom of the six-membered heterocycle. Their optical and redox properties were studied in detail, supported by in-depth theoretical calculations. The modularity of the synthetic strategy allowed the establishment of structure–property relationships for this class of compounds and an OLED based on a blue phosphinine emitter could be developed for the first time.     

The Effect of Aminated Carbon Nanotube and Phosphorus Pentoxide on the Thermal Stability and Flame Retardant Properties of the Acrylonitrile–Butadiene–Styrene

Multi-walled carbon nanotubes (MWCNT) have been successfully functionalized with amino groups. In order to improve the thermal stability of the polymer nanocomposite, aminated-MWCNTs were added to acrylonitrile–butadiene–styrene (ABS). The influence of MWCNT and phosphorus pentoxide nanostructures on the flame retardancy of the ABS matrix was studied using UL-94 test. The results show that the MWCNT nanostructure can’t enhance the flame retardancy of the ABS matrix but synergism of MWCNT and P₂O₅ can effectively improve the flame retardancy of the nanocomposite.     

Properties of χ-alumina as related to catalysis

-Alumina was synthesized by thermal decomposition of aluminium(III) isopropoxide, and its properties were investigated. The change in its surface area with increasing calcination temperature resembled that of -alumina. Both aluminas had the same acid strength, and their activities in isomerization of 1-butene were the same. -Alumina as a support for molybdenum catalyst in the epoxidation of allyl alcohol also behavedin the same manner as -alumina. Thus -alumina has almost the same catalytic properties as -alumina.     

Theoretical Study of the Photochemical Reaction Mechanism of Bicyclo [4.1.0 ] heptane

IntroductionPhotochemical reactions, which involve a three-membered ring, have been of great interest to experi-mental photochemists[1—10]. A main reason for thisphenomenon is that the cyclopropane ring exhibits somereaction characteristics of double bon…     

Mono-Aryl/Alkylthio-Substituted (Hetero)acenes of Exceptional Thermal and Photochemical Stability by the Thio-Friedel–Crafts/Bradsher Cyclization Reaction

The highly substituted mono-aryl/alkylthio-(hetero)acenes prepared in this study have been found to be thermally more stable (T_decomp.=331–354 °C) than the known di-aryl/alkylthio-substituted acenes by an average of 25 °C. They are also much more photostable at 254 and 365 nm (in both argon and air) than the parent anthracene and other reported anthracenes. The most photostable aryl/alkylthio-anthracenes at 254 nm were found to be 60–70 (in air) and 130 (in argon) times more stable in solution than the unsubstituted anthracene, and much more stable than known EDG/EWG-substituted anthracenes (EDG=electron-donating group, EWG=electron-withdrawing group) with an extended aromatic core. Furthermore, the acenes showed significantly higher photostability at 365 nm in both air and argon. The anthracenes were obtained by the novel thio-Friedel–Crafts/Bradsher cyclization reaction of hitherto unknown [o-(1,3-dithian-2-yl)aryl](aryl)methyl thioethers. The developed approach provides a general access to mono-aryl/alkylthio-substituted (hetero)acene frameworks containing at least three fused (hetero)aromatic rings. The characteristic feature of this approach, which leads to highly substituted acenes, is that the substituents, unlike in other methods, may be introduced at an early stage of the synthesis. DFT and TD-DFT calculations confirmed the stabilizing role of the aryl/alkylthio substituent in the mono-aryl/alkylthio-substituted anthracenes, which are the most stable anthracenes prepared to date. Their high photostability is mainly due to the quenching of singlet oxygen by the acene and the quenching of the acene S₁ state by molecular oxygen.