Tumor-Targeted Squaraine Dye for Near-Infrared Fluorescence-Guided Photodynamic Therapy.

Many efforts have been made to develop near-infrared (NIR) fluorescent dyes with high efficiency for the NIR laser-induced phototherapy of cancer. However, the low tumor targetability and high nonspecific tissue uptake of NIR dyes in vivo limit their applications in preclinical cancer imaging and therapy. Among the various NIR dyes, squaraine (SQ) dyes are widely used due to their high molar extinction coefficient, intense fluorescence, and excellent photostability. Previously, benzoindole-derived SQ (BSQ) was prepared by incorporating carboxypentyl benzoindolium end groups into a classical SQ backbone, followed by conjugating with cyclic RGD peptides for tumor-targeted imaging. In this study, we demonstrate that the structure-inherent tumor-targeting BSQ not only shows a high fluorescence quantum yield in serum but also exhibits superior reactive oxygen species (ROS) generation capability under the 671 nm laser irradiation for effective photodynamic therapy (PDT) in vitro and in vivo. Without targeting ligands, the BSQ was preferentially accumulated in tumor tissue 24 h post-injection, which was the optimal timing of the laser irradiation to induce increments of ROS production. Therefore, this work provides a promising strategy for the development of photodynamic therapeutic SQ dyes for targeted cancer therapy.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Design and Synthesis of Novel Squaraine-Based Fluorescent Probe for Far-Red Detection of Chymotrypsin Enzyme.

Chymotrypsin, a crucial enzyme in human digestion, catalyzes the breakdown of milk proteins, underscoring its significance in both health diagnostics and dairy quality assurance. Addressing the critical need for rapid, cost-effective detection methods, we introduce a groundbreaking approach utilizing far-red technology and HOMO-Förster resonance energy transfer (FRET). Our novel probe, SQ-122 PC, features a unique molecular design that includes a squaraine dye (SQ), a peptide linker, and SQ moieties synthesized through solid-phase peptide synthesis. Demonstrating a remarkable quenching efficiency of 93.75% in a tailored H2O:DMSO (7:3) solvent system, our probe exhibits absorption and emission properties within the far-red spectrum, with an unprecedented detection limit of 0.130 nM. Importantly, our method offers unparalleled selectivity towards chymotrypsin, ensuring robust and accurate enzyme detection. This pioneering work underscores the immense potential of far-red-based homo-FRET systems in enabling the sensitive and specific detection of chymotrypsin enzyme activity. By bridging the gap between cutting-edge technology and biomedical diagnostics, our findings herald a new era of enzyme sensing, promising transformative advancements in disease diagnosis and dairy quality control.

An on-off-on fluorescent probe for the detection of glyphosate based on a Cu2+-assisted squaraine dye sensor.

The herbicide glyphosate, N-(phosphonomethyl)glycine, has been widely used in the past 40 years, and has had many adverse effects on human health. Here, we constructed a convenient "on-off-on" fluorescent platform for detection of glyphosate via Cu2+ modulated squaraine dye fluorescence quenching. The squaraine dye F-0 exhibited strong fluorescence, which could be quenched by the addition of Cu2+. However, the addition of glyphosate restored the fluorescence intensity of F-0 due to the formation of a Cu2+-glyphosate complex. F-0 was utilized as a fluorescent probe for the quantitative detection of glyphosate, with the lowest detection limit of 13.16 nmol L-1. Furthermore, this method demonstrated high selectivity and anti-interference capabilities. The successful monitoring of glyphosate in real samples was achieved using this detection strategy.

Cardiogenic shock in a 28-year-old woman associated with sibutramine use.

A 28-year-old woman collapsed in her home, and her companion rushed to call emergency services. Upon arrival, a physician performed CPR and endotracheal intubation, successfully restoring her voluntary heart rhythm. However, while en route to the hospital, ventricular fibrillation recurred. Despite the restoration of her voluntary rhythm through electrical defibrillation, she remained in a comatose state, which eventually led to multiple organ failures. Family members revealed that she had a 2-month history of taking diet pills. Histological examination revealed cardiomyocyte necrosis, contraction band necrosis, interstitial hemorrhage, collagen deposition, interstitial fiber proliferation, and myofiber remodeling. Analysis of blood and urine using GC-MS and LC-MS detected sibutramine and its primary metabolites, M1 and M2, which were consistent with the composition of the medication she was taking. The deceased was in good health with no underlying heart disease. The above information confirmed that the cause of her death was sibutramine.

Is cognitive behavioral therapy more effective than pharmacotherapy for binge spectrum disorders? A systematic review and meta-analysis.

OBJECTIVES: Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains underutilized. Cognitive behavioral therapy is the recommended first-line treatment, but pharmacotherapy may be easier to access. INTERVENTIONS: Meta-analytic evidence directly comparing cognitive behavioral therapy with pharmacotherapy is lacking. We aimed to compare the effects of cognitive behavioral therapy interventions with any pharmacological treatment for binge spectrum disorders. We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov and reference lists for randomized controlled trials comparing cognitive behavioral therapy with any pharmacotherapy for bulimia nervosa/binge eating disorder and performed pairwise meta-analytic evaluations. PRIMARY OUTCOMES: Primary outcomes are remission and frequency of binges. Secondary outcomes are frequency of purges, response, eating disorder psychopathology, weight/body mass index, depression, anxiety, quality of life and dropouts. RESULTS: Eleven randomized controlled trials comparing cognitive behavioral therapy with fluoxetine/imipramine/desipramine/methylphenidate/sibutramine were identified (N = 531). Cognitive behavioral therapy was superior to antidepressants in terms of remission, frequency of binges and eating disorder psychopathology. There were no statistically significant differences for any of the individual cognitive behavioral therapy vs drug comparisons in terms of response/depression/anxiety/weight/quality of life/dropouts. Cognitive behavioral therapy was not superior to sibutramine/methylphenidate for the primary outcomes. CONCLUSIONS: Data are scarce, comparisons underpowered and, considering the inherent methodological limitations of psychotherapy trials, questions arise regarding the presumed superiority of cognitive behavioral therapy. Further research is needed.

Thiolation for Enhancing Photostability of Fluorophores at the Single-Molecule Level.

Fluorescent probes are essential for single-molecule imaging. However, their application in biological systems is often limited by the short photobleaching lifetime. To overcome this, we developed a novel thiolation strategy for squaraine dyes. By introducing thiolation of the central cyclobutene of squaraine (thio-squaraine), we observed a ≈5-fold increase in photobleaching lifetime. Our single-molecule data analysis attributes this improvement to improved photostability resulting from thiolation. Interestingly, bulk measurements show rapid oxidation of thio-squaraine to its oxo-analogue under irradiation, giving the perception of inferior photostability. This discrepancy between bulk and single-molecule environments can be ascribed to the factors in the latter, including larger intermolecular distances and restricted mobility, which reduce the interactions between a fluorophore and reactive oxygen species produced by other fluorophores, ultimately impacting photobleaching and photoconversion rate. We demonstrate the remarkable performance of thio-squaraine probes in various imaging buffers, such as glucose oxidase with catalase (GLOX) and GLOX+trolox. We successfully employed these photostable probes for single-molecule tracking of CD56 membrane protein and monitoring mitochondria movements in live neurons. CD56 tracking revealed distinct motion states and the corresponding protein fractions. This investigation is expected to propel the development of single-molecule imaging probes, particularly in scenarios where bulk measurements show suboptimal performance.

Cost-Effectiveness Modeling of Prostate-Specific Membrane Antigen Positron Emission Tomography with Piflufolastat F 18 for the Initial Diagnosis of Patients with Prostate Cancer in the United States.

BACKGROUND AND OBJECTIVES: Piflufolastat F 18 is a novel prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer that is superior to standard of care (SOC) imaging for the initial staging of prostate cancer and the detection of biochemical recurrence. As piflufolastat F 18 has been approved in the United States (US) for this indication, this modeling study assessed the cost effectiveness of piflufolastat F 18 versus fluciclovine F-18, gallium68-PSMA-11 (PSMA 11), and SOC imaging (a mix of bone scans, computed tomography, and magnetic resonance imaging) for the diagnosis and staging of prostate cancer from a US healthcare system perspective. PERSPECTIVE: A US third-party payer perspective was used, which for this population reflects a mix of commercial and Medicare, considering only direct healthcare costs. SETTING: This study utilized a tertiary healthcare setting. METHODS: A decision tree was used to map the diagnostic/treatment pathway, consisting of the proportion of patients with local, regional, distant, or no disease; prostate-specific antigen (PSA) ≤ 1.0 or > 1.0; and accuracy of imaging modalities. A Markov model predicted the long-term outcomes of disease progression according to treatment decisions. Inputs to the model were informed by data from the OSPREY and CONDOR clinical trials, public data, and the literature. Treatment mix included active surveillance, radiation therapy, prostatectomy, androgen deprivation therapy (ADT), and radiation therapy + ADT, informed by expert opinion. Outcomes included life-years (LY), quality-adjusted life-years (QALY), and the incremental cost-effectiveness ratio (ICER). All costs were reported in 2021 US dollars, using the US Bureau of Labor Statistics Consumer Price Index. A willingness-to-pay (WTP) threshold of $150,000 was considered cost effective, consistent with the upper range used as the standard for price benchmarks by the Institute for Clinical and Economic Review. The robustness of the base-case results was assessed in deterministic and probabilistic sensitivity analyses. RESULTS: Over a lifetime horizon, piflufolastat F 18 had the greatest effectiveness in terms of LYs (6.80) and QALYs (5.33); for the comparators, LYs ranged from 6.58 (SOC) to 6.76 (PSMA 11) and QALYs ranged from 5.12 (SOC) and 5.30 (PSMA 11). Piflufolastat F 18 was more cost effective compared with fluciclovine F 18, PSMA 11, and SOC, with ICERs of $21,122, $55,836, and $124,330 per QALY gained, respectively. Piflufolastat F 18 was associated with the greatest net monetary benefit ($627,918) compared with the other options at a WTP threshold of $150,000. The results of the deterministic and probabilistic sensitivity analyses supported the robustness of the base-case results. CONCLUSIONS: This study suggests that piflufolastat F 18 is a cost-effective diagnostic option for men with prostate cancer in the US, with higher associated LY, QALY, and greater net monetary benefit than fluciclovine F 18, PSMA 11, and SOC imaging.

Initial Experience with the Radiotracer 18F-Fluciclovine PET/CT in Ovarian Cancer.

OBJECTIVE: Early and accurate staging of ovarian cancer is paramount to disease survival. Conventional imaging including FDG PET/CT are limited in the evaluation of small metastatic lesions. 18F-Fluciclovine has minimal urine and bowel excretion allowing optimal visualization of the abdomen and pelvis. This study examines 18F-fluciclovine uptake in known primary and recurrent ovarian cancer. METHODS: Seven patients with a confirmed diagnosis of epithelial ovarian cancer underwent 18F-fluciclovine PET/CT imaging. Forty-one (41) lesions were identified with 18F-fluciclovine and confirmed to be true positive (n = 41). We aim to explore if 18F-fluciclovine uptake in ovarian lesions were greater than background uptake of bone marrow, blood pool, and bladder. Quantification analysis was performed to determine max and mean standard uptake values (SUVmax and SUVmean) of known and suspected lesions compared to SUVmean uptake of background structures. RESULTS: 18F-Fluciclovine demonstrated 100% sensitivity (41/41) for uptake in known ovarian lesions. The average SUVmax (±SD) uptake of known ovarian lesions was 5.9 (±2.6) and 5.1 (±2.0) on early and delayed images, respectively. The average tumor SUVmax to SUVmean of background (±SD) (T:B) ratios on early and delay were 1.9 (±0.8), 2.1 (±0.9) for marrow; 3.8 (±1.8), 3.4 (±1.5) for aorta; and 8.4 (±4.3), 1.5 (±1.7) for bladder, respectively. CONCLUSION: 18F-Fluciclovine uptake in malignant ovarian lesions was above background levels suggesting its feasibility in the imaging of ovarian cancer. Due to increasing tracer washout via the urinary bladder over time, early imaging at 4 min post injection is favorable.

Effect of hydrophilicity-imparting substituents on exciton delocalization in squaraine dye aggregates covalently templated to DNA Holliday junctions.

Molecular aggregates exhibit emergent properties, including the collective sharing of electronic excitation energy known as exciton delocalization, that can be leveraged in applications such as quantum computing, optical information processing, and light harvesting. In a previous study, we found unexpectedly large excitonic interactions (quantified by the excitonic hopping parameter Jm,n) in DNA-templated aggregates of squaraine (SQ) dyes with hydrophilic-imparting sulfo and butylsulfo substituents. Here, we characterize DNA Holliday junction (DNA-HJ) templated aggregates of an expanded set of SQs and evaluate their optical properties in the context of structural heterogeneity. Specifically, we characterized the orientation of and Jm,n between dyes in dimer aggregates of non-chlorinated and chlorinated SQs. Three new chlorinated SQs that feature a varying number of butylsulfo substituents were synthesized and attached to a DNA-HJ via a covalent linker to form adjacent and transverse dimers. Various characteristics of the dye, including its hydrophilicity (in terms of log Po/w) and surface area, and of the substituents, including their local bulkiness and electron withdrawing capacity, were quantified computationally. The orientation of and Jm,n between the dyes were estimated using a model based on Kühn-Renger-May theory to fit the absorption and circular dichroism spectra. The results suggested that adjacent dimer aggregates of all the non-chlorinated and of the most hydrophilic chlorinated SQ dyes exhibit heterogeneity; that is, they form a mixture of dimers subpopulations. A key finding of this work is that dyes with a higher hydrophilicity (lower log Po/w) formed dimers with smaller Jm,n and large center-to-center dye distance (Rm,n). Also, the results revealed that the position of the dye in the DNA-HJ template, that is, adjacent or transverse, impacted Jm,n. Lastly, we found that Jm,n between symmetrically substituted dyes was reduced by increasing the local bulkiness of the substituent. This work provides insights into how to maintain strong excitonic coupling and identifies challenges associated with heterogeneity, which will help to improve control of these dye aggregates and move forward their potential application as quantum information systems.

Photophysical Characterization and Biointeractions of NIR Squaraine Dyes for in Vitro and in Vivo Bioimaging.

The increasing demand for reliable near-infrared (NIR) probes exhibiting enduring fluorescence in living systems and facile compatibility with biomolecules such as peptides, antibodies or proteins is driven by the increasing use of NIR imaging in clinical diagnostics. To address this demand, a series of carboxy-functionalized unsymmetrical squaraine dyes (SQ-27, SQ-212, and SQ-215) along with non-carboxy-functionalized SQ-218 absorbing and emitting in the NIR wavelength range were designed and synthesized followed by photophysical characterization. This study focused on the impact of structural variations in the alkyl chain length, carboxy functionality positioning, and spacer chain length on dye aggregation and interaction with bovine serum albumin (BSA) as a model protein. In phosphate buffer (PB), the absorption intensity of the dyes markedly decreased accompanied by pronounced shoulders indicative of dye aggregation, and complete fluorescence quenching was seen in contrast to organic solvents. However, in the presence of BSA in PB, there was a enhancement in absorption intensity while regaining the fluorescence coupled with a remarkable increase in the intensity with increasing BSA concentrations, signifying the impact of dye-BSA interactions on preventing aggregation. Further analysis of Job's plot unveiled a 2:1 interaction ratio between BSA and all dyes, while the binding studies revealed a robust binding affinity (Ka) in the order of 107/mol. SQ-212 and SQ-215 were further tested for their in vitro and in vivo imaging capabilities. Notably, SQ-212 demonstrated nonpermeability to cells, while SQ-215 exhibited easy penetration and prominent cytoplasmic localization in in vitro studies. Injection of the dyes into laboratory mice showcased their efficacy in visualization, displaying stable and intense fluorescence in tissues without toxicity, organ damage, or behavioral changes. Thus, SQ-212 and SQ-215 are promising candidates for imaging applications, holding potential for noninvasive cellular and diagnostic imaging as well as biomarker detection when coupled with specific vectors in living systems.

Green and economic flame retardant prepared by the one-step method for polylactic acid.

Resolving the flammability of poly(L-lactic acid) (PLA) while ensuring its environmental friendliness and preserving key flame retardancy and mechanical properties represents a critical challenge. We have successfully developed a highly efficient and environmentally friendly flame retardant called Hexamethylenediamine tetramethylene phosphonic acid amine (HDME). The flame retardancy of PLA/HDME composites was significantly improved, as indicated by the LOI value of 29.1 % and UL-94 V-0 rating for PLA/3.5 HDME with only 3.5 % HDME addition. The results show a 23.4 % reduction in the total heat release (THR), a 40.0 % increase in the time to ignition (TTI), and a 21.2 % increase in the flame propagation index (FPI) compared to original PLA. Flame retardant mechanism of HDME involves the gas phase, condensed phase, and interrupted heat exchange effects. The HDME also preserved the original mechanical properties of PLA, with the elongation at break and tensile strength retention of PLA/3.5 HDME reaching 93.05 % and 89.65 %. This work provides a simple and efficient method for flame retardant modification of PLA, which can expand its application scope.

Tissue and Circulating MicroRNAs 378 and 142 as Biomarkers of Obesity and Its Treatment Response.

Promising approaches to the treatment of obesity include increasing energy expenditure and slowing down fibrogenesis of adipose tissue. The neurotransmitter reuptake inhibitor sibutramine affects appetite and activates lipolysis in a catecholaminergic way. MicroRNAs (miRs) are considered as biomarkers of molecular genetic mechanisms underlying various processes. The profile of a number of miRs is altered in obesity, both in the circulation and in adipose tissue. The aim of this study was to assess the expression levels of miRs (hsa-miR-378a-3p, hsa-miR-142-3p) by real-time polymerase chain reaction in subcutaneous adipose tissue (SAT) and in plasma in patients with different degrees and duration of obesity and during sibutramine therapy. This study included 51 obese patients and 10 healthy subjects with normal weight who formed a control group. The study found that, before treatment, obese patients had no significant difference in the expression level of miR-378 in SAT and plasma compared to the control group, while the expression of miR-142 was significantly decreased in SAT and increased in plasma. A significant elevation in miR-378 expression level was noted in patients with first-degree obesity and duration of less than 10 years, and the decline in miR-142 increased with the duration of obesity. These data indicate a maximal increase in the expression of the adipogenesis inducer miR-378 in the early stages of obesity, a progressive decrease in the expression of the fibrogenesis inhibitor miR-142 in SAT with growth of duration of obesity and the likely presence of antifibrogenic effects of sibutramine realized through miR-142 activation.

Stereochemistry-Driven Interactions of α,γ-Peptide Ligands with the Neuropeptide Y Y4-Receptor.

The G-protein-coupled Y4-receptor (Y4R) and its endogenous ligand, pancreatic polypeptide (PP), suppress appetite in response to food intake and, thus, are attractive drug targets for body-weight control. The C-terminus of human PP (hPP), T32-R33-P34-R35-Y36-NH2, penetrates deep into the binding pocket with its tyrosine-amide and di-arginine motif. Here, we present two C-terminally amidated α,γ-hexapeptides (1a/b) with sequence Ac-R31-γ-CBAA32-R33-L34-R35-Y36-NH2, where γ-CBAA is the (1R,2S,3R)-configured 2-(aminomethyl)-3-phenylcyclobutanecarboxyl moiety (1a) or its mirror image (1b). Both peptides bind the Y4R (Ki of 1a/b: 0.66/12 nM) and act as partial agonists (intrinsic activity of 1a/b: 50/39%). Their induced-fit binding poses in the Y4R pocket are unique and build ligand-receptor contacts distinct from those of the C-terminus of the endogenous ligand hPP. We conclude that energetically favorable interactions, although they do not match those of the native ligand hPP, still guarantee high binding affinity (with 1a rivaling hPP) but not the maximum receptor activation.

Reductive Photocycloreversion of Cyclobutane Dimers Triggered by Guanines.

The quest for simple systems achieving the photoreductive splitting of four-membered ring compounds is a matter of interest not only in organic chemistry but also in biochemistry to mimic the activity of DNA photorepair enzymes. In this context, 8-oxoguanine, the main oxidatively generated lesion of guanine, has been shown to act as an intrinsic photoreductant by transferring an electron to bipyrimidine lesions and provoking their cycloreversion. But, in spite of appropriate photoredox properties, the capacity of guanine to repair cyclobutane pyrimidine dimer is not clearly established. Here, dyads containing the cyclobutane thymine dimer and guanine or 8-oxoguanine are synthesized, and their photoreactivities are compared. In both cases, the splitting of the ring takes place, leading to the formation of thymine, with a quantum yield 3.5 times lower than that for the guanine derivative. This result is in agreement with the more favored thermodynamics determined for the oxidized lesion. In addition, quantum chemistry calculations and molecular dynamics simulations are carried out to rationalize the crucial aspects of the overall cyclobutane thymine dimer photoreductive repair triggered by the nucleobase and its main lesion.

Chromium-Catalyzed Diastereoselective Synthesis of Conformationally Constrained Spirotetrahydroquinolines.

We report the diastereoselective cyclization of anilines with cyclobutanones and congeners by chromium catalysis. This reaction can link two strained four-membered rings with tetrahydroquinolines by forming four bonds in a diastereocontrolled manner, forming medicinally interesting cyclobutane-fused and constrained spirotetrahydroquinolines (STHQs) and complex multiple spiro carbon-containing polyazacycles. The constrained STHQs have been used as versatile feedstocks to derive a range of oxygen-, nitrogen-, and thio-substituted spiro analogues, and dioxygen-incorporated spiroazacycles.

Construction of Fully Substituted Cyclobutanes by Tandem Reaction of 1,4-Diyn-3-ols and Anhydrides.

A concise and efficient synthesis of fully substituted cyclobutane derivatives from 1,4-diyn-3-ols and anhydrides was developed. Mechanistic studies indicated that a tandem esterification, isomerization to give allenyl ester, and homointermolecular [2+2] cycloaddition might be involved. The features of this protocol are its operational practicality, mild reaction conditions, and high regio- and stereoselectivity, and it is a readily accessible gram-scale synthesis.

Migration from Photochemistry to Electrochemistry for [2 + 2] Cycloaddition Reaction.

Cyclobutane scaffolds are incorporated in several valuable natural and bioactive products. However, non-photochemical ways to synthesize cyclobutanes have scarcely been investigated. Herein, based on the principles of the electrosynthesis technique, we introduce a novel electrochemical approach for attaining cyclobutanes by a simple [2 + 2] cycloaddition of two electron-deficient olefins in the absence of photocatalysts or metal catalysts. This electrochemical strategy provides a suitable condition for synthesizing tetrasubstituted cyclobutanes with a variety of functional groups in good to excellent efficiency, compatible with gram-scale synthesis. In contrast to previous challenging methods, this approach strongly focuses on the convenient accessibility of the reaction instruments and starting materials for preparing cyclobutanes. Readily accessible and inexpensive electrode materials are firm evidence to prove the simplicity of this reaction. In addition, mechanistic insight into the reaction is obtained by investigation of the CV spectra of the reactants. Also, the structure of a product is identified by X-ray crystallography.

Transannular C-H functionalization of cycloalkane carboxylic acids.

Cyclic organic molecules are common among natural products and pharmaceuticals1,2. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates3-5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C-H activation offers an ideal route to these compounds. However, the site-selective C-H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C-H palladation. Here we report that two classes of ligands-quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)-enable transannular γ-methylene C-H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple ß-C-H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3-5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.

New "Destruction Seek to Survive" Strategy Based on a Serum Albumin Assembly with a Squaraine Molecule for the Detection of Peroxynitrite.

Peroxynitrite (ONOO-), a kind of active nitrogen species, plays an important role in biological systems. Overproduction of ONOO- is closely related to the pathogenesis of many diseases. Therefore, it is necessary to quantify intracellular ONOO- for differentiating health and disease states. Fluorescent probes with near-infrared (NIR) fluorescence can detect ONOO- with high sensitivity and selectivity. However, there is an inevitable problem that many NIR fluorophores are easily oxidized by ONOO- to give a false-negative result. To avoid this problem, herein, we ingeniously propose a "destruction to seek to survive" strategy to detect ONOO-. Two NIR squaraine (SQ) dyes were connected together to form a fluorescent probe (SQDC). This method utilizes the destructive effect of peroxynitrite on one of the SQ moieties of SQDC to eliminate the steric hindrance, enabling the other "survived" SQ segment to enter the hydrophobic cavity of bovine serum albumin (BSA) via the well-known host-guest interactions. The encapsulation of albumin protects the "survived" SQ from further attack of ONOO-. As a result, a NIR fluorescence turn-on response coming from the host-guest interaction between BSA and the "survived" SQ escaped from SQDC was found, which can be used for the detection of ONOO-. The assembly of SQDC mixed with BSA can be located in mitochondria to detect endogenous and exogenous ONOO- sensitively in living cells. As a proof-of-concept method, it is envisioned that this novel detection strategy with a simple assembly would become a powerful means for the detection of ONOO- when employing NIR fluorophores.