Redox-Regulated In Situ Seed-Induced Assembly of Peptides.

Morphology-transformational self-assembly of peptides allows for manipulation of the performance of nanostructures and thereby advancing the development of biomaterials. Acceleration of the morphological transformation process under a biological microenvironment is important to efficiently implement the tailored functions in living systems. Herein, we report redox-regulated in situ seed-induced assembly of peptides via design of two co-assembled bola-amphiphiles serving as a redox-resistant seed and a redox-responsive assembly monomer, respectively. Both of the peptides are able to independently assemble into nanoribbons, while the seed monomer exhibits stronger assembling propensity. The redox-responsive monomer undergoes morphological transformation from well-defined nanoribbons to nanoparticles. Kinetics studies validate the role of the assembled inert monomer as the seeds in accelerating the assembly of the redox-responsive monomer. Alternative addition of oxidants and reductants into the co-assembled monomers promotes the redox-regulated assembly of the peptides facilitated by the in situ-formed seeds. The reduction-induced assembly of the peptide could also be accelerated by in situ-formed seeds in cancer cells with a high level of reductants. Our findings demonstrate that through precisely manipulating the assembling propensity of co-assembled monomers, the in situ seed-induced assembly of peptides could be achieved. Combining the rapid assembly kinetics of the seed-induced assembly with the common presence of redox agents in a biological microenvironment, this strategy potentially offers a new method for developing biomedical materials in living systems.

The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.

Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu2+ to Cu1+ triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu+2 → Cu+1 redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.

Tetrasulfide bond boosts the anti-tumor efficacy of dimeric prodrug nanoassemblies.

Dimeric prodrug nanoassemblies (DPNAs) stand out as promising strategies for improving the efficiency and safety of chemotherapeutic drugs. The success of trisulfide bonds (-SSS-) in DPNAs makes polysulfide bonds a worthwhile focus. Here, we explore the comprehensive role of tetrasulfide bonds (-SSSS-) in constructing superior DPNAs. Compared to trisulfide and disulfide bonds, tetrasulfide bonds endow DPNAs with superlative self-assembly stability, prolonged blood circulation, and high tumor accumulation. Notably, the ultra-high reduction responsivity of tetrasulfide bonds make DPNAs a highly selective "tumor bomb" that can be ignited by endogenous reducing agents in tumor cells. Furthermore, we present an "add fuel to the flames" strategy to intensify the reductive stress at tumor sites by replenishing exogenous reducing agents, making considerable progress in selective tumor inhibition. This work elucidates the crucial role of tetrasulfide bonds in establishing intelligent DPNAs, alongside the combination methodology, propelling DPNAs to new heights in potent cancer therapy.

The role of photorespiration in preventing feedback regulation via ATP synthase in Nicotiana tabacum.

Photorespiration consumes substantial amounts of energy in the forms of adenosine triphosphate (ATP) and reductant making the pathway an important component in leaf energetics. Because of this high reductant demand, photorespiration is proposed to act as a photoprotective electron sink. However, photorespiration consumes more ATP relative to reductant than the C3 cycle meaning increased flux disproportionally increases ATP demand relative to reductant. Here we explore how energetic consumption from photorespiration impacts the flexibility of the light reactions in nicotiana tabacum. Specifically, we demonstrate that decreased photosynthetic efficiency (ϕII ) at low photorespiratory flux was related to feedback regulation at the chloroplast ATP synthase. Additionally, decreased ϕII at high photorespiratory flux resulted in the accumulation of photoinhibition at photosystem II centers. These results are contrary to the proposed role of photorespiration as a photoprotective electron sink. Instead, our results suggest a novel role of ATP consumption from photorespiration in maintaining ATP synthase activity, with implications for maintaining energy balance and preventing photodamage that will be critical for plant engineering strategies.

Dioxygen Reduction and Bioinspired Oxidations by Non-heme Iron(II)-α-Hydroxy Acid Complexes.

ConspectusAerobic organisms involve dioxygen-activating iron enzymes to perform various metabolically relevant chemical transformations. Among these enzymes, mononuclear non-heme iron enzymes reductively activate dioxygen to catalyze diverse biological oxidations, including oxygenation of C-H and C═C bonds and C-C bond cleavage with amazing selectivity. Several non-heme enzymes utilize organic cofactors as electron sources for dioxygen reduction, leading to the generation of iron-oxygen intermediates that act as active oxidants in the catalytic cycle. These unique enzymatic reactions influence the design of small molecule synthetic compounds to emulate enzyme functions and to develop bioinspired catalysts for performing selective oxidation of organic substrates with dioxygen. Selective electron transfer during dioxygen reduction on iron centers of synthetic models by a sacrificial reductant requires appropriate design strategies. Taking lessons from the role of enzyme-cofactor complexes in the selective electron transfer process, our group utilized ternary iron(II)-α-hydroxy acid complexes supported by polydentate ligands for dioxygen reduction and bioinspired oxidations. This Account focuses on the role of coordinated sacrificial reductants in the selective electron transfer for dioxygen reduction by iron complexes and highlights the versatility of iron(II)-α-hydroxy acid complexes in affecting dioxygen-dependent oxidation/oxygenation reactions. The iron(II)-coordinated α-hydroxy acid anions undergo two-electron oxidative decarboxylation concomitant with the generation of reactive iron-oxygen oxidants. A nucleophilic iron(II)-hydroperoxo species was intercepted in the decarboxylation pathway. In the presence of a Lewis acid, the O-O bond of the nucleophilic oxidant is heterolytically cleaved to generate an electrophilic iron(IV)-oxo-hydroxo oxidant. Most importantly, the oxidants generated with or without Lewis acid can carry out cis-dihydroxylation of alkenes. Furthermore, the electrophilic iron-oxygen oxidant selectively hydroxylates strong C-H bonds. Another electrophilic iron(IV)-oxo oxidant, generated from the iron(II)-α-hydroxy acid complexes in the presence of a protic acid, carries out C-H bond halogenation by using a halide anion.Thus, different metal-oxygen intermediates could be generated from dioxygen using a single reductant, and the reactivity of the ternary complexes can be tuned using external additives (Lewis/protic acid). The catalytic potential of the iron(II)-α-hydroxy complexes in performing O2-dependent oxygenations has been demonstrated. Different factors that govern the reactivity of iron-oxygen oxidants from ternary iron(II) complexes are presented. The versatile reactivity of the oxidants provides useful insights into developing catalytic methods for the selective incorporation of oxidized functionalities under environmentally benign conditions using aerial oxygen as the terminal oxidant.

Green synthesized silver nanoparticles using the plant-based reducing agent Matricaria chamomilla induce cell death in colorectal cancer cells.

OBJECTIVE: There is a need to treat cancer cells with safe and natural nanoparticles to avoid the side effects of chemotherapeutic agents. Chamomile is considered a safe, natural plant with anticancer activity. We synthesize simple, inexpensive, and eco-friendly silver nanoparticles (SNs) using Chamomile (CHM) to tune their anticancer properties. MATERIALS AND METHODS: SN-CHM was synthesized by reducing 1 mM silver nitrate aqueous solution in 100 mL with the aqueous ethanolic flower extract of CHM (18 mg/mL, w/v). The reaction proceeded overnight at 600 rpm and 28°C. SN-CHM was characterized for their % yield, average diameter, charge, morphology, and silver release. Moreover, SN-CHM was investigated for its antioxidant and anticancer activities at 200 µg/mL and 5 mg/ mL, respectively. RESULTS: A 59.12% yield and a uniform SN-CHM size of 115 ± 3.1 nm with a ζ-potential of -27.67 ± (-3.92) mv were observed. The UV-visible absorption showed shifts from 379.5 to 383.5 nm for CHM and SN-CHM, respectively. Moreover, Ag+ was ultimately released from SN-CHM after 5 h. Fourier Transform Infrared Spectroscopy (FT-IR) showed characteristic absorption peaks of CHM and produced SN-CHM. Furthermore, SN-CHM showed moderate antioxidant activity. SN-CHM inhibited the % viability of SW620 and HT-29 cell lines at 20 µM. SN-CHM may also greatly upregulate the apoptotic gene BAX while considerably downregulating the anti-apoptotic genes BCL2 and BCL-Xl. CONCLUSIONS: CHM can be a safe soft drink, especially when conjugated with Ag ions as anticancer NPs. SN-CHM is considered potent anticancer activity against SW620, and HT-29 cell lines.

Selective Reduction of Cysteine Mutant Antibodies for Site-Specific Antibody-Drug Conjugates.

Developing site-specific conjugation technologies for antibody-drug conjugates (ADCs) aims to produce more homogeneous and controlled drug-loaded ADCs to reduce variability and thereby improve the therapeutic index. This article presents a technology that uses cysteine mutant antibodies and mild phosphine-based reductants to prepare site-specific ADCs. The two types of cysteine mutant antibodies, designated C6v1 and C6v2, have one of the interchain disulfide-forming cysteines in the Fab region in the light chain (LC214) or in the heavy chain (HC220) substituted by alanine (or other amino acids), respectively. Certain phosphine-based reductants were found to selectively reduce the "unpaired" cysteines, at the heavy chain (HC220) for C6v1 or at the light chain (LC214) for C6v2 while keeping the interchain disulfide bonds in the hinge region intact, resulting in 90% of DAR2 species and more than 95% of the desired specific conjugation at HC or LC following conjugation to maleimide moieties. The reduction method shows consistent selectivity toward various C6v1 or C6v2 antibody backbones. Sensitivity toward buffer pH for some reductants can be used to optimize reductant reactivity and selectivity. The technology can be further expanded to generate site-specific DAR4 or dual-payload ADCs based on C6v1 or C6v2 antibodies. This technology offers a method to control drug-loading and conjugation sites using a mild one-pot process, as compared to the reduction-oxidation methods used in technologies such as THIOMAB, and shows superior DAR profiles and process simplification as compared to other selective reduction methods.

Tannin complexation with metal ions and its implication on human health, environment and industry: An overview.

Tannins, also known as plant polyphenols (PPs), are secondary metabolites widely existing in higher plants and are a kind of natural renewable resource with wide distribution, variety and quantity. Tannin has become an important class of fine chemicals due to the easily modified molecular structure and the properties of antibacterial and antioxidant, combining with protein and complexing with metal ion. Besides being used for tanning leather, tannins are also widely used in wood adhesive, concrete water-reducing agents, oil drilling fluid viscosity-reducing agents, pharmaceutical, mineral processing, water treatment, gas desulfurization, metal anticorrosion, wood anticorrosion, printing and dyeing, liquor clarification, oil antioxidant, daily chemical products and other products preparation. There are two groups of tannins: condensed tannins (CTs) (flavonoid-derived proanthocyanidins) and hydrolysable tannins (HTs) (gallic acid ester-derived). Tannins can form complexes with metals through the ortho-dihydroxyphenolic group(s), especially with transition metals. The structure-activity relationships, stoichiometry, and origin of the insolubility of which were emphasized. Furthermore, this paper proposed an in-depth discussion of the associations of tannins-metal complexes in human health, environment and industries.

Iron(III)-(1,10-Phenanthroline) Complex Can Enhance Ferrate(VI) and Ferrate(V) Oxidation of Organic Contaminants via Mediating Electron Transfer.

Recent research has primarily focused on the utilization of reductants as activators for Fe(VI) to generate high-valent iron species (Fe(IV)/Fe(V)) for the degradation of emerging organic contaminants (EOCs). However, a significant drawback of this approach arises from the reaction between reductants and ferrates, leading to a decrease in oxidation capacity. This study introduces a novel discovery that highlights the potential of the iron(III)-(1,10-phenanthroline) (Fe(III)-Phen) complex as an activator, effectively enhancing the degradation of EOCs by Fe(VI) and augmenting the overall oxidation capacity of Fe(VI). The degradation of EOCs in the Fe(VI)/Fe(III)-Phen system is facilitated through two mechanisms: a direct electron transfer (DET) process and electron shuttle action. The DET process involves the formation of a Phen-Fe(III)-Fe(VI)* complex, which exhibits a stronger oxidation ability than Fe(VI) alone and can accept electrons directly from EOCs. On the other hand, the electron shuttle process utilizes Fe(III)-Phen as a redox mediator to transfer electrons from EOCs to Fe(VI) through the Fe(IV)/Fe(III) or Fe(IV)/Fe(II)/Fe(III) cycle. Moreover, the Fe(III)-Phen complex can improve the utilization efficiency of Fe(V) by preventing its self-decay. This study's findings may present a viable option for utilizing an effective catalyst to enhance the oxidation of EOCs by Fe(VI) and Fe(V).

Green Synthesis of Metal and Metal Oxide Nanoparticles: A Review of the Principles and Biomedical Applications.

In recent years, interest in nanotechnology has increased exponentially due to enhanced progress and technological innovation. In tissue engineering, the development of metallic nanoparticles has been amplified, especially due to their antibacterial properties. Another important characteristic of metal NPs is that they enable high control over the features of the developed scaffolds (optimizing their mechanical strength and offering the controlled release of bioactive agents). Currently, the main concern related to the method of synthesis of metal oxide NPs is the environmental impact. The physical and chemical synthesis uses toxic agents that could generate hazards or exert carcinogenicity/environmental toxicity. Therefore, a greener, cleaner, and more reliable approach is needed. Green synthetic has come as a solution to counter the aforementioned limitations. Nowadays, green synthesis is preferred because it leads to the prevention/minimization of waste, the reduction of derivatives/pollution, and the use of non-toxic (safer) solvents. This method not only uses biomass sources as reducing agents for metal salts. The biomolecules also cover the synthesized NPs or act as in situ capping and reducing agents. Further, their involvement in the formation process reduces toxicity, prevents nanoparticle agglomeration, and improves the antimicrobial activity of the nanomaterial, leading to a possible synergistic effect. This study aims to provide a comprehensive review of the green synthesis of metal and metal oxide nanoparticles, from the synthesis routes, selected solvents, and parameters to their latest application in the biomedical field.

Dual-Targeting PET Tracers Enable Enzyme-Mediated Self-Assembly for the PET Imaging of Legumain Activity.

Legumain, a lysosomal cysteine protease overexpressed in a variety of tumors, has been considered a promising biomarker for various cancers. Precise detection of legumain activity in the lysosome represents an important strategy for early diagnosis and prognosis of tumors. Small-molecule probes with the property of target-enabled self-assembly hold great potential for molecular imaging. In this study, we reported two dual-targeting radiotracers ([18F]SF-AAN-M and [18F]SF-AAN-HEM) with a property of legumain-mediated self-assembly for positron emission tomography (PET) imaging. Both the radiotracers were synthesized with high labeling yield (>50%) and the radiochemical purity was over 99% via one-step straightforward 18F-labeling. Both tracers were efficiently activated by the reducing agent and legumain to self-assemble into aggregates and showed enhanced retention in legumain-overexpressed MDA-MB-468 cells and tumors, indicating that the introduction of lysosome-targeting morpholine increased the tumor uptake and extended the retention of radiotracers in legumain-overexpressed tumors. In addition, [18F]SF-AAN-HEM with a hydrophilic (histidine-glutamate)3 tag displayed significantly reduced liver uptake with no conspicuous reduction in tumor uptake, affording high signal-to-noise ratios (tumor/liver and tumor/muscle). All of these results suggest that dual-targeting tracer [18F]SF-AAN-HEM could provide a promising tool for in vivo monitoring legumain activity in tumors.

Model based assessment of food and acid reducing agent effects on oral absorption of mezigdomide (CC-92480), a novel cereblon E3 ligase modulator.

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell-killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4-3.2 mg mezigdomide with full PK profiles collected. A two-compartment linear PK model with first-order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18 h-1 (interoccasion variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), respectively. High-fat meal increased oral bioavailability by ~30% and PPI co-administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose-exposure relationship in HSs. The PK model suggests a modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.

NIR light, pH, and redox-triple responsive nanogels for controlled release.

Herein we report a novel spiropyran (SP)-based organic-inorganic composite nanogel (NG), which was prepared using upconverting nanoparticles, spiropyran, acrylic acid and N,N'-bis(acryloyl)cystamine (BAC) compounds under emulsion polymerisation. Compared with other polymer nanoparticles, the crosslinked multi-stimulus responsive nanogels can adjust the release rate by altering more of the parameters and this can meet the needs of a complex biological environment to control the release of drugs. Doxorubicin hydrochlorides were used as a simulated drug to test the drug loading performance and controllable drug release performance of the composite NGs. Under near-infrared light (NIR) irradiation, an acidic environment or a reducing agent, the delivery of the loaded drugs was by controlled release over 24 hours. Under mild triple stimulation (NIR light, pH 6, and 4 mM reducing agent), the loaded drug could be released more efficiently. The organic-inorganic composite NGs with highly-efficient and controllable release performance for loaded drugs provide many choices for novel stimulus responsive nanocarriers.

Biogeochemical modelling to assess benzene removal by biostimulation in aquifers containing natural reductants.

Biostimulation of aquifers contaminated with gasoline spills is vigorously affected by the biogeochemical environment existing there. In this study, biostimulation of benzene is simulated using a 2D coupled multispecies biogeochemical reactive transport (MBRT) model. The model is implemented at an oil spill site near a hypothetical aquifer containing natural reductants. Multiple electron acceptors are introduced to promote faster biodegradation rate. However, after reaction with natural reductants, it reduces the number of available electron acceptors, acidifies the subsurface environment, and inhibits bacterial growth. These mechanisms are assessed using seven coupled MBRT models sequentially. The finding of the present analysis reveals that biostimulation has caused a substantial drop in concentration of benzene and is efficient in reducing its penetration depth. The results also shows that the intervention of natural reductants in the biostimulation process is slightly diminished by pH adjustment of aquifers. When the pH level in aquifer changes from acidic pH 4 to neutral pH 7, it is observed that the biostimulation rate of benzene as well as microbial activity increases. Electron acceptors consumption is more at neutral pH. Overall, it can be inferred from zeroth-order spatial moment and sensitivity analyses that retardation factor, inhibition constant, pH, and dispersivity in vertical direction significantly affect benzene biostimulation in aquifers.

Chemical doping to control the in-situ formed doping structure in light-emitting electrochemical cells.

The initial operation of a light-emitting electrochemical cell (LEC) constitutes the in-situ formation of a p-n junction doping structure in the active material by electrochemical doping. It has been firmly established that the spatial position of the emissive p-n junction in the interelectrode gap has a profound influence on the LEC performance because of exciton quenching and microcavity effects. Hence, practical strategies for a control of the position of the p-n junction in LEC devices are highly desired. Here, we introduce a "chemical pre-doping" approach for the rational shifting of the p-n junction for improved performance. Specifically, we demonstrate, by combined experiments and simulations, that the addition of a strong chemical reductant termed "reduced benzyl viologen" to a common active-material ink during LEC fabrication results in a filling of deep electron traps and an associated shifting of the emissive p-n junction from the center of the active material towards the positive anode. We finally demonstrate that this chemical pre-doping approach can improve the emission efficiency and stability of a common LEC device.

The effect of food and acid-reducing agents on the pharmacokinetic profile of capivasertib: Results from a randomized, crossover study.

AIMS: This two-part, adaptive study assessed the effect of food and an acid-reducing agent (rabeprazole) on the pharmacokinetics (PK) and safety of capivasertib, a potent AKT inhibitor, in clinical development for cancer treatment. METHODS: In Part 1, healthy participants (n = 24) were randomized to receive single-dose capivasertib after overnight fasting, a high-fat, high-calorie meal and with rabeprazole postovernight fasting in one of six treatment sequences. Based on Part 1 results, a new group of participants (n = 24) were randomized (Part 2) to receive capivasertib after overnight fasting, a low-fat, low-calorie meal and modified fasting (food restricted from 2 h before dosing to 1 h postdose) in one of six treatment sequences. Blood samples were collected for PK analyses. RESULTS: Following a high-fat, high-calorie meal, capivasertib exposure increased versus overnight fasting (geometric mean ratio [GMR] [90% confidence interval (CI)]: area under the concentration-time curve [AUCinf ] 1.32 [1.22, 1.43], maximum concentration [Cmax ] 1.23 [1.08, 1.41]), but was comparable to that postmodified fasting (GMR: AUCinf 1.13 [0.99, 1.29], Cmax 0.85 [0.70, 1.04]). AUCinf was similar and Cmax was lower with/without rabeprazole (GMR: AUCinf 0.94 [0.87, 1.02]), Cmax 0.73 [0.64, 0.84]). Capivasertib exposure was similar after a low-fat, low-calorie meal versus overnight fasting (GMR: AUCinf 1.14 [1.05, 1.25], Cmax 1.21 [0.99, 1.48]) or modified fasting (GMR: AUCinf 0.96 [0.88, 1.05], Cmax 0.86 [0.70, 1.06]). Safety was consistent with that in larger trials. CONCLUSIONS: This study demonstrates that administering capivasertib with food or acid-reducing agents does not lead to clinically relevant PK or safety profile changes.

Polyphenol Oxidase Products Are Priming Agents for LPMO Peroxygenase Activity.

Polyphenol oxidases catalyze the hydroxylation of monophenols to diphenols, which are reducing agents for lytic polysaccharide monooxygenases (LPMOs) in their degradation of cellulose. In particular, the polyphenol oxidase MtPPO7 from Myceliophthora thermophila converts lignocellulose-derived monophenols, and under the new perspective of the peroxygenase reaction catalyzed by LPMOs, we aim to differentiate the role of the catalytic products of MtPPO7 in priming and fueling of LPMO activity. Exemplified by the activity of MtPPO7 towards guaiacol and by using the benchmark LPMO NcAA9C from Neurospora crassa we show that MtPPO7 catalytic products provide the initial electron for the reduction of Cu(II) to Cu(I) but cannot provide the required reducing power for continuous fueling of the LPMO. The priming reaction is shown to occur with catalytic amounts of MtPPO7 products and those compounds do not generate substantial amounts of H2 O2 in situ to fuel the LPMO peroxygenase activity. Reducing agents with a low propensity to generate H2 O2 can provide the means for controlling the LPMO catalysis through exogenous H2 O2 and thereby minimize any enzyme inactivation.

The current status in computational exploration of Pt(IV) prodrug activation by reduction.

Octahedral PtIV complexes are considered highly promising candidates for overcoming some shortcomings of clinically approved PtII drugs. PtIV compounds, owing to their inertia, appear to be capable of resisting premature aquation and undesired binding to essential plasma proteins and have shown remarkable potential for both oral administration and for reducing side effects. Additionally, their pharmacological properties can be finely tuned by choosing appropriate axial ligands. The reduction inside the cell by biological reducing agents to the correponding active cytotoxic PtII species, accompanied by the loss of the axial ligands, is considered an essential step of their mechanism and has been extensively studied. However, a detailed understanding of the mechanism by which PtIV prodrugs are activated, which should be highly beneficial for their proper design, is lacking, and many contradictory results continue to be collected. In the hope of contributing to the advancement of knowledge in this field, this perspective focuses on the insights gained from computational studies carried out with the aim of finding answers to the many still open questions concerning the reduction of PtIV complexes in biological environments.

Radiolabeled gemcitabine hydrochloride as an imaging agent for lung cancer: Radiolabeling, quality control and cell incorporation studies.

The development of new drugs that can specifically screen tumors is a global need. When it comes to lung cancer, which is the second main cause of cancer-related deaths, early detection of lung tumors using appropriate imaging is very important. In this study, gemcitabine hydrochloride (GCH) was radiolabeled with [99mTc]Tc under different conditions (changing reducing agent, antioxidant agent, incubation time, pH, [99mTc]Tc activity) and radiolabeling activity (quality control) using Radio Thin Layer Chromatography and paper electrophoresis. The results showed that the most stable complex ([99mTc]Tc-GCH) was prepared using 0.015 mg of stannous chloride as a reducing agent, 0.01 mg of ascorbic acid as an antioxidant and 37 MBq activity at pH 7.4 after 15 min of incubation time. The complex remained stable for 6 h. Cell incorporation studies showed a six-fold higher uptake of [99mTc]Tc-GCH in cancer (A-549) cells (38.42 ± 1.53) than healthy (L-929) cells (6.11 ± 0.17) have shown that it can. In addition, the different behaviors of R/H-[99mTc]Tc confirmed the specificity of this newly developed radiopharmaceutical. Although these studies are preliminary, it has been concluded that [99mTc]Tc-GCH may be a candidate drug for use in nuclear medicine, particularly in the diagnosis of lung cancer.

Hydroperoxyl radical (HOO•) as a reducing agent: unexpected synergy with antioxidants. A review.

This review highlights the progress made in recent years in harnessing the peculiar chemistry of the hydroperoxyl, or perhydroxyl, radical (HOO•) during lipid peroxidation, particularly with regard to its interaction with antioxidants. The HOO• radical, the protonated form of superoxide, plays an important role in the propagation and termination of lipid peroxidation in nonaqueous systems. However, differently from alkylperoxyl (ROO•) radicals that have only oxidizing ability, HOO• has a two-faced oxidizing and reducing activity. The HOO• radical can reduce the radical of the antioxidant (phenols and aromatic amines) by H-atom transfer (A• + HOO• ⟶ AH + O2) thus increasing the length of the inhibition period and the effectiveness of the antioxidant. The simultaneous presence of HOO• and ROO• radicals triggers the catalytic antioxidant activity of quinones and nitroxides and explains the antioxidant activity of melanin-like polymers. The HOO• radical can be formed by fragmentation of ROO• radicals deriving from amines, alcohols, substituted alkenes and may be present at low concentrations in many oxidizing systems. Pro-aromatic compounds, like the natural essential oil component γ-terpinene, are the most effective sources of HOO• and behave as co-antioxidants in the presence of nitroxides or quinones. The future developments and applications of HOO• chemistry in the context of the inhibition of autoxidation are also discussed.