Dual-Responsive Near-Infrared BODIPY-Based Fluorescent Probe for the Detection of F- and HClO in Organisms.

Fluoride anions (F-) play a crucial role in human physiological processes. However, excessive intake of F- would affect oxygen metabolism and promote the generation of oxygen-free radicals. Hence, it is essential to develop a precise and efficient fluorescent probe for visualizing F--induced oxidative stress. In this work, we developed the first bifunctional BODIPY-based fluorescent probe dfBDP with p-tert-butyldimethylsilanolate benzyl thioether as the sensing site for the detection of F- and HClO via two distinct reactions, the self-immolative removal and the thioether oxidation, which generate the sensing products with two nonoverlap fluorescence bands: 800-1200 and 500-750 nm, respectively. The probe dfBDP displays rapid response, high specificity, and sensitivity for the detection of F- (LOD, 316.2 nM) and HClO (LOD, 33.9 nM) in vitro. Cellular imaging reveals a correlation between F--induced oxidative stress and the upregulation of HClO. Finally, probe dfBDP was employed to detect F- and HClO in mice under the stimulation of F-. The experimental results display that the level of HClO elevates in the liver of mice.

Arylacryl amides: Design, synthesis and the protection against cisplatin-induced acute kidney injury via TLR4/STING/NF-κB pathway.

Arylpropionic ester scaffold was found as anti-inflammatory agents for the treatment and prevention of acute kidney injury (AKI). To further study the structure-activity relationship (SAR) of this scaffold, a series of acryl amides were designed, synthesized, and evaluated their anti-inflammation. Of these, compound 9d displayed the protective effect on renal tubular epithelial cells to significantly enhance the survival rate through inhibiting NF-κB phosphorylation and promoting cell proliferation in cisplatin-induced HK2 cells. Furthermore, 9d can interact with TLR4 to inhibit TLR4/STING/NF-κB pathway in the RAW264.7 cell. In vivo AKI mice model, 9d significantly downregulated the level of serum creatinine (Scr), blood urea nitrogen (BUN) and the inflammatory factors (IL-1ß, IL-6, TNF-α) to improve kidney function. Morphological and KIM-1 analyses showed that 9d alleviated cisplatin-induced tubular damage. In a word, 9d was a promising lead compound for preventive and therapeutic of AKI.

Transient Absorption Spectroscopic Investigation of the Photocyclization-Deprotection Reaction of 3',5'-Dimethoxybenzoin Fluoride.

The 3',5'-dimethoxybenzoin (DMB) system has been widely investigated as a photoremovable protecting group (PRPG) for the elimination of various functional groups and has been applied in many fields. The photolysis of DMB fluoride leads to a highly efficient photocyclization-deprotection reaction, resulting in a high yield of 3',5'-dimethoxybenzofuran (DMBF) in a MeCN solution, while there is a competitive reaction that produces DMB in an aqueous solution. The yield of DMB increased as the volume ratio of water increased. To understand the solvent effect of the photolysis of selected DMB-based compounds, a combination of femtosecond to nanosecond transient absorption spectroscopies (fs-TA and ns-TA), nanosecond time-resolved resonance Raman spectroscopy (ns-TR3) and quantum chemical calculation was employed to study the photophysical and photochemical reaction mechanisms of DMB fluoride in different solutions. Facilitated by the bichromophoric nature of DMB fluoride with electron-donating and -withdrawing chromophores, the cyclized intermediates could be found in a pure MeCN solution. The deprotection of a cyclic biradical intermediate results in the simultaneous formation of DMBF and a cyclic cation species. On the other hand, in aqueous solution, fs-TA experiments revealed that α-keto cations could be observed after excitation directly, which could easily produce the DMB through the addition of a hydroxyl within 8.7 ps. This work provides comprehensive photo-deactivation mechanisms of DMB fluoride in MeCN and aqueous conditions and provides critical insights regarding the biomedical application of DMB-based PRPG compounds.

Discovery of (E)-2-Methoxyethene-1-sulfonyl Fluoride for the Construction of Enaminyl Sulfonyl Fluoride.

A new sulfonyl fluoride reagent (E)-2-methoxyethene-1-sulfonyl fluoride (MeO-ESF) was developed and successfully applied for the construction of enaminyl sulfonyl fluoride (N-ESF). This protocol provides highly atom-economical access to diverse N-ESF and produces CH3OH as the sole byproduct under mild and environmentally benign conditions.

Preoperative CT findings and prognosis of pulmonary sarcomatoid carcinoma: comparison with conventional NSCLC of similar tumor size.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) but differs in terms of treatment strategies compared with conventional-NSCLC (c-NSCLC). However, preoperative CT differentiation between PSC and c-NSCLC remains a challenge. This study aimed to explore the CT findings and prognosis of PSC compared with c-NSCLC of similar tumor size. METHODS: Clinical data and CT findings of 31 patients with PSC and 87 patients with c-NSCLC were retrospectively analyzed. Clinical data included sex, age, and smoking history. CT findings included tumor size, tumor location, calcification, vacuole/cavity, pleural invasion, mean CT value, and low-attenuation area (LAA) ratio. Kaplan‒Meier curves and log-rank tests were used for survival analysis. A Cox regression model was constructed to evaluate prognostic risk factors associated with overall survival (OS). The Spearman correlation among clinicoradiological outcomes were analyzed. RESULTS: The mean tumor size of PSC and c-NSCLC were both 5.1 cm. The median survival times of PSC and c-NSCLC were 8 months and 34 months, respectively (P < 0.001). Calcification and vacuoles/cavities were rarely present in PSC. Pleural invasion occurred in both PSC and c-NSCLC (P = 0.285). The mean CT values of PSC and c-NSCLC on plain scan (PS), arterial phase (AP), and venous phase (VP) were 30.48 ± 1.59 vs. 36.25 ± 0.64 Hu (P = 0.002), 43.26 ± 2.96 vs. 58.71 ± 1.65 Hu (P < 0.001) and 50.26 ± 3.28 vs. 64.24 ± 1.86 Hu (P < 0.001), the AUCs were 0.685, 0.757 and 0.710, respectively. Compared to c-NSCLC, PSC had a larger LAA ratio, and the AUC was 0.802, with an optimal cutoff value of 20.6%, and the sensitivity and specificity were 0.645 and 0.862, respectively. Combined with the mean CT value and LAA ratio, AP + VP + LAA yielded the largest AUC of 0.826. The LAA ratio were not independent risk factors for PSC in this study. LAA ratio was negatively correlated with PS (r = -0.29), AP (r = -0.58), and VP (r = -0.66). LAA showed a weak positive correlation with tumor size(r = 0.27). CONCLUSIONS: PSC has a poorer prognosis than c-NSCLC of similar tumor size. The mean CT value and LAA ratio contributes to preoperative CT differentiation of PSC and c-NSCLC.

Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors.

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO2F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (Ki = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aß1 - 42-induced cognitive impairment, significantly prevented the effects of Aß1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Crystal structures of FadD32 and pks13-ACP domain from Corynebacterium diphtheriae.

Mycolic acids (MAs) are unique components of cell envelope of Mycobacterium or Corynebacterium and are key factors of their virulence to human. In order to develop new anti-Tuberculosis (TB) drugs, many efforts have paid on investigation of structures and functions of proteins involved in the biosynthesis pathway of MAs. FadD32 and polyketide synthase 13 (pks13) catalyze the last step of MAs synthesis. Here we present the crystal structures of FadD32 with substrates and holo-form of ACP-domain from Corynebacterium diphtheriae. The crystal structures and in vitro biochemical assays provide new insights into the assembly of FadD32 and pks13.

Novel FabI inhibitor disrupts the biofilm formation of MRSA through down-regulating the expression of quorum-sensing regulatory genes.

OBJECTIVES: The aim of this study was to explore the antibiofilm and antivirulence efficacy of benzylaniline 4k against MRSA. METHODS: The clinical MRSA strains were identified and used to evaluate their potential to form biofilm using crystal violet assay. The minimal inhibitory concentration (MIC) was determined using broth microdilution method. The expression of genes was detected using quantitative real-time PCR (qRT-PCR). Rabbit blood hemolytic assay was used to observe the inhibitory ability of alpha-hemolysin (Hla). RESULTS: Compound 4k showed potent antibacterial activity against 16 clinical MRSA with an MIC50 of 1.25 mg/L and MIC90 of 2.25 mg/L. The value of minimum biofilm eradication concentration (MBEC) against MRSA2858 biofilm was of 1.5 mg/L, close to its MIC, superior to those of vancomycin and erythromycin. Compound 4k eradicated the formation of biofilm through inhibiting the gene expression of branched-chain fatty acid synthesis, down-regulating the expression of quorum-sensing (QS) regulatory genes (norA, agrA, icaA, hla), decreasing the level of hemolysis in a dose-dependent manner, and inhibiting rabbit blood hemolysis by 86.9% at a concentration of 1.25 mg/L. In a mouse model of abdominal infection, compound 4k was more effective than vancomycin in reducing bacterial load. CONCLUSIONS: These results suggested that compound 4k could be developed as promising an anti-MRSA agent through affecting quorum-sensing system.

Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer's disease.

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 µM and 6.59 µM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 µM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aß1 - 42-induced cognitive impairment, and significantly prevented the effects of Aß1 - 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.

18ß-Glycyrrhetinic acid monoglucuronide (GAMG) alleviates single-walled carbon nanotubes (SWCNT)-induced lung inflammation and fibrosis in mice through PI3K/AKT/NF-κB signaling pathway.

Carbon nanotubes (CNTs) have become far and wide used in a number of technical and merchant applications as a result of substantial advances in nanotechnology, therein single-walled carbon nanotubes (SWCNT) are one of the most promising nanoparticles. Inhaling CNTs has been linked to a variety of health problems, including lung fibrosis. Glycyrrhetinic acid 3-O-mono-ß-D-glucuronide (GAMG), a natural sweetener, has anti-inflammatory and antioxidant capacities. The purpose of this study was to evaluate the potential for GAMG to alleviate SWCNT-induced lung inflammation and fibrosis. During days 3-28 after SWCNT intratracheal administration, we observed a remarkable increase of IL-1ß, IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) on day 3 and collagen deposition on day 28. GAMG treatment remarkably ameliorated SWCNT-induced pulmonary fibrosis and attenuated SWCNT-induced inflammation and collagen deposition, and suppressed the activation of PI3K/AKT/NF-κB signaling pathway in the lungs. Therefore, GAMG has a therapeutic potential for the treatment of SWCNT-induced pulmonary fibrosis. Targeting PI3K/AKT/NF-κB signaling pathway may be a potential therapeutic approach to treat pulmonary fibrosis in mice with SWCNT.

Physiology-Based Pharmacokinetic Study on 18ß-Glycyrrhetic Acid Mono-Glucuronide (GAMG) Prior to Glycyrrhizin in Rats.

To understand that 18ß-Glycyrrhetic acid 3-O-mono-ß-D-glucuronide (GAMG) showed better pharmacological activity and drug-like properties than 18ß-Glycyrrhizin (GL); a rapid and sensitive HPLC-MS/MS method was established for the simultaneous determination of GAMG and its metabolite 18ß-Glycyrrhetinic acid (GA) in rat plasma and tissues after oral administration of GAMG or GL. This analytical method was validated by linearity, LLOQ, specificity, recovery rate, matrix effect, etc. After oral administration, GAMG exhibited excellent Cmax (2377.57 ng/mL), Tmax (5 min) and AUC0-T (6625.54 mg/L*h), which was much higher than the Cmax (346.03 ng/mL), Tmax (2.00 h) and AUC0-T (459.32 mg/L*h) of GL. Moreover, GAMG had wider and higher tissue distribution in the kidney, spleen, live, lung, brain, etc. These results indicated that oral GAMG can be rapidly and efficiently absorbed and be widely distributed in tissues to exert stronger and multiple pharmacological activities. This provided a physiological basis for guiding the pharmacodynamic study and clinical applications of GAMG.

Design and synthesis of novel glycyrrhetin ureas as anti-inflammatory agents for the treatment of acute kidney injury.

To develop new anti-inflammatory drugs for the prevention and treatment of acute kidney injury, a series of novel glycyrrhetic ureas were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Compounds 5r-5u (2.04, 2.50, 3.25 and 2.48 µM, respectively) with acidic or neutral amino acid showed potent anti-inflammatory activity (IC50 = 2-3 µM for NO inhibition), amongst them, compound 5r also inhibited tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a dose-dependent manner. In cisplatin-induced AKI mice model, compound 5r significantly reduced the level of pro-inflammatory factors, ameliorated the pathological damage of kidney tissue, and maintained the normal metabolic capacity.

Structure-activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease.

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 µM for eqBChE, 3.62 µM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH3 > -CH3 > -Cl (-Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aß1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aß1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.

Therapeutic strategies for targeting telomerase in cancer.

Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere-based therapies such as nucleoside analogs, non-nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere-based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

Time-Resolved Spectroscopic Observation of Diphenylnitrenium Ion Reactions with Guanosine.

Arylnitrenium ions have gained attention for their high reactivity toward guanosine, which in some cases has been linked to carcinogenesis. Although many studies have examined covalent addition reactions between arylnitrenium ions and guanosine, there is still some uncertainty regarding the attack position of nitrenium ions on guanosine and its derivatives. In this paper, we employ nanosecond transient absorption and nanosecond time-resolved resonance Raman spectroscopy to investigate the reaction between the N,N-di(4-bromophenyl) nitrenium ion (2) and guanosine. Our time-resolved spectroscopic results and photochemical product analysis results show that the reaction of guanosine with 2 generates an N7 intermediate that subsequently undergoes rearrangement and deprotonation to produce a C8 adduct. Comparing these results to our previous study between the 2-fluorenylnitrenium ion and guanosine indicates that the structure and properties of arylnitrenium ions are able to influence the reaction pathways and intermediate structures.

Design, synthesis and biological evaluation of novel arylpropionic esters for the treatment of acute kidney injury.

Acute kidney injury (AKI) is associated with a strong inflammatory response, and inhibiting the response effectively prevents or ameliorates AKI. A series of novel arylpropionic esters were designed, synthesized and evaluated their biological activity in LPS-stimulated RAW264.7 cells. Novel arylpropionic esters bearing multi-functional groups showed significant anti-inflammatory activity, in which, compound 13b exhibited the most potent activity through dose-dependent inhibiting the production of nitric oxide (NO, IC50 = 3.52 µM), TNF-α and IL-6 (84.1% and 33.6%, respectively), as well as suppressing the expression of iNOS, COX-2 and TLR4 proteins. In C57BL/6 mice with cisplatin-induced AKI, compound 13b improved kidney function, inhibited inflammatory development, and reduced pathological damage of kidney tissues. In brief, this arylpropionic ester scaffold may be developed as anti-inflammatory agents.

Photochemical α-Cleavage Reaction of 3',5'-Dimethoxybenzoin: A Combined Time-Resolved Spectroscopy and Computational Chemistry Study.

Benzoin is one of the most commonly used photoinitiators to induce free radical polymerization. Here, improved benzoin properties could be accomplished by the introduction of two methoxy substituents, leading to the formation of 3',5'-dimethoxybenzoin (DMB) which has a higher photo-cleavage quantum yield (0.54) than benzoin (0.35). To elucidate the underlying reaction mechanisms of DMB and obtain direct information of the transient species involved, femtosecond transient absorption (fs-TA) and nanosecond transient absorption (ns-TA) spectroscopic experiments in conjunction with density functional theory/time-dependent density functional theory (DFT/TD-DFT) calculations were performed. It was found that the photo-induced α-cleavage (Norrish Type I reaction) of DMB occurred from the nπ* triplet state after a rapid intersystem crossing (ISC) process (7.6 ps), leading to the generation of phenyl radicals on the picosecond time scale. Compared with Benzoin, DMB possesses two methoxy groups which are able to stabilize the alcohol radical and thus result in a stronger driving force for cleavage and a higher quantum yield of photodissociation. Two stable conformations (cis-DMB and trans-DMB) at ground state were found via DFT calculations. The influence of the intramolecular hydrogen bond on the α-cleavage of DMB was elaborated.

Design, synthesis and biological evaluation of tricyclic pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one scaffolds as selective BuChE inhibitors.

Based on the structural analysis of tricyclic scaffolds as butyrylcholinesterase (BuChE) inhibitors, a series of pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one derivatives were designed, synthesized and evaluated for their acetylcholinesterase (AChE) and BuChE inhibitory activity. Compounds with 5-carbonyl and 7- or/and 9-halogen substitutions showed potential BuChE inhibitory activity, among which compounds 6a, 6c and 6g showed the best BuChE inhibition (IC50 = 1.06, 1.63 and 1.63 µM, respectively). The structure-activity relationship showed that the 5-carbonyl and halogen substituents significantly influenced BuChE activity. Compounds 6a and 6g were found nontoxic, lipophilic and exhibited remarkable neuroprotective activity and mixed-type inhibition against BuChE (Ki = 7.46 and 3.09 µM, respectively). Docking studies revealed that compound 6a can be accommodated into BuChE via five hydrogen bonds, one Pi-Sigma interaction and three Pi-Alkyl interactions.

pH Dependent Photodeprotection of Formaldehyde: Homolytic C-C Scission in Acidic Aqueous Solution versus Heterolytic C-C Scission in Basic Aqueous Solution.

The photodeprotection of formaldehyde was investigated for 3-(1-hydroxypropan-2-yl)benzophenone (3-HPBP) with ultrafast time-resolved spectroscopy. The femtosecond transient absorption results indicated the singlet excited state of 3-HPBP transformed efficiently into its triplet state by a fast intersystem crossing. In acidic (pH = 0) and basic (pH = 12.5) aqueous solutions, the triplet intermediate was a key precursor for the deprotection of formaldehyde via two different pathways. However, little photodeprotection was observed in neutral (pH = 7) aqueous solution where the triplet intermediate appeared to undergo a proton coupled electron transfer process to form a ketyl radical transient. The important benzylic biradical intermediates seen in the acidic and basic aqueous solutions were identified by time-resolved resonance Raman spectra whose vibrational frequency patterns were consistent with DFT calculation results for the benzylic biradical intermediate. The results here indicate that the ß-carbon alcohol group of the triplet state 3-HPBP is deprotonated in basic aqueous solutions and this leads to a heterolytic C-C bond cleavage to deprotect formaldehyde and produce the benzylic carbanion triplet state species, whereas protonation of the carbonyl moiety of the triplet state 3-HPBP leads to direct generation of a benzylic biradical intermediate and the deprotection of formaldehyde in acidic aqueous solutions via a homolytic C-C bond cleavage.

Competition between "Meta Effect" Photochemical Reactions of Selected Benzophenone Compounds Having Two Different Substituents at Meta Positions.

Recent studies conducted on some "meta effect" photochemical reactions focused on aromatic carbonyls having a substitution on one meta position of the benzophenone (BP) and anthraquinone parent compound. In this paper, two different substitutions were introduced with one at each meta position of the BP parent compound to investigate possible competition between different types of meta effect photochemistry observed in acidic solutions containing water. The photochemical pathways of 3-hydroxymethyl-3'-fluorobenzophenone (1) and 3-fluoro-3'-methylbenzophenone (2) were explored in several solvents, including acidic water-containing solutions, using time-resolved spectroscopic experiments and density functional theory computations. It is observed that 1 can undergo a photoredox reaction and 2 can undergo a meta-methyl deprotonation reaction in acidic water-containing solutions. Comparison of these results to those previously reported for the analogous BP derivatives that contain only one substituent at a meta position indicates the introduction of electron-donating (such as hydroxyl) and electron-withdrawing groups (such as F) on the meta positions of BP can influence the meta effect photochemical reactions. It was found that involvement of an electron-donating moiety facilitates the meta effect photochemical reactions by stabilizing the crucial reactive biradical intermediate associated with the meta effect photochemical reactions.