Direct synthesis of carbamates, thiocarbamates, and ureas from Boc-protected amines: a sustainable and efficient approach.

In the quest for sustainable and efficient synthetic methodologies within medicinal chemistry, the synthesis of carbamates and their derivatives holds a pivotal role due to their widespread application in bioactive compounds. This investigation unveils a novel methodology for the straightforward transformation of Boc-protected amines into carbamates, thiocarbamates, and ureas, utilizing tert-butoxide lithium as the sole base. This approach effectively obviates the necessity for hazardous reagents and metal catalysts, presenting marked enhancements compared to traditional synthetic pathways. Notably, the method demonstrates facile scalability to gram-level production. This study contributes to the advancement of sustainable synthetic methodologies, offering a more benign and efficient alternative for the synthesis of key chemical intermediates with implications for broad pharmaceutical and agrochemical applications.

RPTOR mutation: a novel predictor of efficacious immunotherapy in melanoma.

Identifying biomarkers to evaluate the therapeutic effect of immune checkpoint inhibitors (ICIs) is crucial. Regulatory Associated Protein of MTOR Complex 1 (RPTOR), one of the genes in the mTOR pathway, plays a role in regulating tumor progression. However, the connection between RPTOR mutation and the efficacy of ICIs in melanoma remains unclear. The data of ICIs-treated melanoma patients in discovery (n = 384) and validation (n = 320) cohorts were obtained from cBioPortal databases. The genomic data in the two cohorts was used to investigate the connection between RPTOR mutation and immunotherapy efficacy. The underlying mechanisms were explored based on data from the The Cancer Genome Atlas (TCGA)-skin cutaneous melanoma (SKCM) cohort. Compared to melanoma patients with RPTOR wildtype (RPTOR-WT), RPTOR-mutation (RPTOR-Mut) patients achieved prolonged overall survival (OS) in both discovery cohort (median OS of 49.3 months vs. 21.7 months; HR = 0.41, 95% CI: 0.18-0.92; P = 0.026) and validation cohorts (not reached vs. 42.0 months; HR = 0.34, 95% CI: 0.11-1.06; P = 0.049). RPTOR-Mut melanoma patients exhibited a higher objective response rate (ORR) than RPTOR-WT patients in the discovery cohort (55.0% vs. 29.0%, P = 0.022). RPTOR-Mut patients exhibited higher TMB than RPTOR-WT patients in both discovery and validation cohorts (P < 0.001). RPTOR-Mut melanoma patients had an increased number of DNA damage response (DDR) mutations in TCGA-SKCM cohort. Immune cell infiltration analysis suggested that activated CD4 memory T cells were more enriched in RPTOR-Mut tumors. RPTOR-Mut melanoma patients had higher expression levels of immune-related genes than the RPTOR-WT patients. Our results suggest that RPTOR mutation could serve as a predictor of effective immunotherapy for melanoma.

Heparin-Mimetic Chitooligosaccharides-Based Monoliths Obtained from C/W Emulsions: Hemocompatibility and Toxin Removal Ability.

Hemoperfusion (HP) is one of the most prominent therapies for treating uremia, hyperbilirubinemia, and acute drug toxicity. The comprehensive performance of currently used porous HP adsorbents needs to be improved due to the impediment to their synthesis strategy. Herein, green carbon dioxide-in-water high internal phase emulsions (C/W HIPEs) were utilized and emulsified with poly(vinyl alcohol) (PVA) for the formation of a heparin-mimetic chitosan oligosaccharides/poly(acrylamide-co-sodium 4-styrenesulfonate) [COS/P(AM-co-SSS)] monolith, which exhibited good mechanical properties, stable swelling performance, hydrophilic properties, anticoagulant effect, and low hemolysis. It showed a strong toxin adsorption capacity (415.2 mg/g for creatinine, 199.3 mg/g for urea, 279.5 mg/g for bilirubin, and 160 mg/g for tetracycline). The adsorption process of porous COS/P(AM-co-SSS) followed the pseudo-second-order kinetic and Langmuir isotherm models. Moreover, the porous materials had a strong electrostatic force on creatinine. The removal of creatinine by simulated in vitro blood perfusion was 80.2% within 30 min. This work provides a green preparation strategy for developing novel HP materials, highlighting their potential application value in blood and environmental purification.

Synthesis and Biological Activities of Oxazolidinone Pleuromutilin Derivatives as a Potent Anti-MRSA Agent.

A series of pleuromutilin derivatives containing an oxazolidinone skeleton were synthesized and evaluated in vitro and in vivo as antibacterial agents. Most of the synthesized derivatives exhibited potent antibacterial activities against three strains of Staphylococcus aureus (including MRSA ATCC 33591, MRSA ATCC 43300, and MSSA ATCC 29213) and two strains of Staphylococcus epidermidis (including MRSE ATCC 51625 and MSSE ATCC 12228). Compound 28 was the most active antibacterial agent in vitro (MIC = 0.008-0.125 µg·mL-1) and exhibited a significant bactericidal effect, low cytotoxicity, and weak inhibition (IC50 = 20.66 µmol·L-1) for CYP3A4, as well as exhibited less possibility to cause bacterial resistance. Furthermore, in vivo activities indicated that the compound was effective in reducing MRSA load in a murine thigh infection model. Moreover, it clearly facilitated the healing of MRSA skin infection and inhibited the secretion of the TNF-α, IL-6, and MCP-1 inflammatory factors in serum. These results suggest that oxazolidinone pleuromutilin is a promising therapeutic candidate for drug-resistant bacterial infections.

Design, Synthesis, and Biological Activity of Thioguanine-Modified Pleuromutilin Derivatives.

Antibiotic overuse has caused the increasingly serious problem of bacterial drug resistance, with numerous marketed antibiotics exhibiting significantly reduced activity against drug-resistant bacteria. Therefore, there is urgent demand for the development of novel antibiotics. Pleuromutilin is a tricyclic diterpene exhibiting antibacterial activity against Gram-positive bacteria and is currently considered the most promising natural antibiotic. In this study, novel pleuromutilin derivatives were designed and synthesized by introducing thioguanine units, and their antibacterial activities against drug-resistant strains were evaluated in vitro and in vivo. Compound 6j was observed to have a rapid bactericidal effect, low cytotoxicity, and potent antibacterial activity. The in vitro results suggest that 6j has a significant therapeutic effect on local infections, and its activity is equal to that of retapamulin, an anti-Staphylococcus aureus pleuromutilin derivative.

Case Report: Response to crizotinib treatment in a patient with advanced non-small cell lung cancer with LDLR-ROS1 fusion.

C-ros oncogene 1 (ROS1) fusion is a pathogenic driver gene in non-small cell lung cancer (NSCLC). Currently, clinical guidelines from the National Comprehensive Cancer Network (NCCN) have recommended molecular pathologic tests for patients with NSCLC, including the detection of the ROS1 gene. Crizotinib is a small molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). In recent years, the efficacy of crizotinib in NSCLC patients with ROS1 fusion has been reported. Here, a 77-year-old woman was diagnosed with stage IVA lung adenocarcinoma harboring a novel low-density lipoprotein receptor (LDLR)-ROS1 fusion variant. This novel LDLR-ROS1 fusion was identified by targeted DNA next-generation sequencing (NGS) panel and then verified by RNA fusion panel based on amplicon sequencing. This patient benefited from subsequent crizotinib therapy and achieved progression-free survival of 15 months without significant toxic symptoms. Our case report recommended a promising targeted therapeutic option for patients with metastatic NSCLC with LDLR-ROS1 fusion and highlighted the importance of genetic testing for accurate treatment.

Organic room-temperature phosphorescence materials for bioimaging.

Organic room-temperature phosphorescence (RTP) materials are currently the focus of research in the field of bioimaging. In comparison with the conventional imaging modalities based on organic fluorescent dyes, RTP materials with long lifetime enable time-resolved imaging to improve the imaging resolution by avoiding autofluorescence. In this review, we will start with summarizing strategies for achieving high performance RTP materials for bioimaging, including the development of RTP-compounds, host-guest doping materials, and supramolecular assemblies. We then discuss the optimization of nanonization processes to obtain RTP nanoparticles with controllable size, high dispersibility, and improved stability. The differences between top-down and bottom-up approaches are further described. Finally, we briefly introduce the emerging methods for preparing RTP materials for bioimaging.

A NIR fluorescent probe for dual imaging of mitochondrial viscosity and FA in living cells and zebrafish.

Formaldehyde (FA) and viscosity play multiple roles in human health and diseases, and viscosity has great regional differences due to the diversity of subcellular organelles. However, it is challenging to achieve dual detection of viscosity and FA in subcellular organelles. Herein, we developed a near infrared (NIR) fluorescent probe FA-Cy, which can simultaneously monitor the viscosity and FA concentration of mitochondria in living cells. The probe could detect mitochondrial viscosity and exogenous and endogenous FA in living cells and zebrafish.

Diastereoselective Synthesis of Dihydrobenzofuran-Fused Spiroindolizidines via Double-Dearomative [3 + 2] Cycloadditions.

Spiroindolizidine oxindoles represent a kind of privileged scaffold in many biologically active natural alkaloids. 2,3-Dihydrobenzofuran derivatives exhibit significant bioactivities in a variety of pharmaceuticals. Herein, we assembled these two privileged fragments into a small molecule via double-dearomative [3 + 2] cycloadditions with pyridinium ylides and 2-nitrobenzofurans. This protocol features remarkable advantages including wide substrate scope, mild condition, high level of diastereoselectivities and yields. Thus, a collection of spiroindolizidine-fused dihydrobenzofurans/indolines were facilely produced efficiently.

A lysosome-targeting fluorescent probe to visualize endogenous and exogenous methylglyoxal in live cells and zebrafish.

The development of a lysosome-targeting fluorescent probe to visualize endogenous and exogenous methylglyoxal (MGO) in live cells has important implications for associated diseases. Herein, a lysosome-targeting fluorescent probe MGO-Naph-A was designed and synthesized to detect MGO with high selectivity. The probe contained naphthalimide as the fluorescent group, o-phenylenediamine as the MGO recognition group, and morpholine as the lysosome targeting group. This fluorescent probe could detect endogenous and exogenous MGO in living cells by precisely targeting and staining lysosomes. It could also detect MGO in living zebrafish. The results showed that the probe MGO-Naph-A has the potential to visualize MGO in lysosomes.

Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-ß-Lactamase Inhibitors.

As one of important mechanisms to ß-lactam antimicrobial resistance, metallo-ß-lactamases (MBLs) have been receiving increasing worldwide attentions. Ambler subclass B1 MBLs are most clinically relevant, because they can hydrolyze almost all ß-lactams with the exception of monobactams. However, it is still lacking of clinically useful drugs to combat MBL-medicated resistance. We previously identified 1H-imidazole-2-carboxylic acid as a core metal-binding pharmacophore (MBP) to target multiple B1 MBLs. Herein, we report structural optimization of 1H-imidazole-2-carboxylic acid and substituents. Structure-activity relationship (SAR) analyses revealed that replacement of 1H-imidazole-2-carboxylic acid with other structurally highly similar MBPs excepting thiazole-4-carboxylic acid resulted in decreased MBL inhibition. Further SAR studies identified more potent inhibitors to MBLs, of which 28 manifested IC50 values of 0.018 µM for both VIM-2 and VIM-5. The microbiological tests demonstrated that the most tested compounds showed improved synergistic effects; some compounds at 1 µg/ml were able to reduce meropenem MIC by at least 16-fold, which will be worth further development of new potent inhibitors particularly targeting VIM-type MBLs.

Continuous-Flow Synthesis of Nitro-o-xylenes: Process Optimization, Impurity Study and Extension to Analogues.

An efficient continuous-flow nitration process of o-xylene at pilot scale was demonstrated. The effects of parameters such as temperature, ratio of H2SO4 to HNO3, H2SO4 concentration, flow rate, and residence time on the reaction were studied. Under the optimal conditions, the yield of products reached 94.1%, with a product throughput of 800 g/h. The main impurities of this continuous-flow nitration process were also studied in detail. Compared with batch process, phenolic impurity decreased from 2% to 0.1%, which enabled the omission of the alkaline solution washing step and thus reduced the wastewater emission. The method was also successfully applied to the nitrification of p-xylene, toluene, and chlorobenzene with good yields.

4,6-Disubstituted-1H-Indazole-4-Amine derivatives with immune-chemotherapy effect and in vivo antitumor activity.

Tryptophan-2,3-dioxygenase (TDO) and indoleamine-2, 3-dioxygenase 1 (IDO1) are the important tumor immune checkpoints and TDO and IDO1 inhibition may present a potential approach to activate the T cell-mediated antitumor immune response during cancer treatment. Herein, we designed and synthesized a series of nitro-aryl 1H-indazole derivatives. SARs analysis showed that the nitro-aryl at the C-4 position of 1H-indazole was beneficial for TDO inhibition and directly tumoricidal effect and the substituents at C-6 position of 1H-indazole significantly affected the activity and selectivity of IDO1/TDO. Among these derivatives, HT-28 and HT-30 demonstrated nanomolar potency and excellent selectivity against TDO with IC50 values of 0.62 µM and 0.17 µM respectively, and HT-37 showed the IDO1 and TDO dual-target inhibitory activity with IC50 values of 0.91 µM and 0.46 µM against IDO1 and TDO. Moreover, HT-28 showed the significant tumoricidal effect on six tumor cell lines, while HT-30 and HT-37 had almost no cytotoxic activity on these tumor cells. In the CT-26 allograft BALB/c mice, HT-28 had the significant in vivo antitumor activity at a lower dose. IHC staining assay indicated that HT-28 could reduce the expression of Foxp3 and enhance the expression of CD8 and TNF-α in tumor tissue. In summary, we developed a difunctional monomer with immune-chemotherapy effect to obtain the better in anti-tumor activity.

One-Pot Route from Halogenated Amides to Piperidines and Pyrrolidines.

Piperidine and pyrrolidine derivatives are important nitrogen heterocyclic structures with a wide range of biological activities. However, reported methods for their construction often face problems of requiring the use of expensive metal catalysts, highly toxic reaction reagents or hazardous reaction conditions. Herein, an efficient route from halogenated amides to piperidines and pyrrolidines was disclosed. In this method, amide activation, reduction of nitrile ions, and intramolecular nucleophilic substitution were integrated in a one-pot reaction. The reaction conditions were mild and no metal catalysts were used. The synthesis of a variety of N-substituted and some C-substituted piperidines and pyrrolidines became convenient, and good yields were obtained.

Identification of key genes and biological pathways in Chinese lung cancer population using bioinformatics analysis.

BACKGROUND: Identification of accurate prognostic biomarkers is still particularly urgent for improving the poor survival of lung cancer patients. In this study, we aimed to identity the potential biomarkers in Chinese lung cancer population via bioinformatics analysis. METHODS: In this study, the differentially expressed genes (DEGs) in lung cancer were identified using six datasets from Gene Expression Omnibus (GEO) database. Subsequently, enrichment analysis was conducted to evaluate the underlying molecular mechanisms involved in progression of lung cancer. Protein-protein interaction (PPI) and CytoHubba analysis were performed to determine the hub genes. The GEPIA, Human Protein Atlas (HPA), Kaplan-Meier plotter, and TIMER databases were used to explore the hub genes. The receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of hub genes. Reverse transcription quantitative PCR (qRT-PCR) was used to validate the expression levels of hub genes in 10 pairs of lung cancer paired tissues. RESULTS: A total of 499 overlapping DEGs (160 upregulated and 339 downregulated genes) were identified in the microarray datasets. DEGs were mainly associated with pathways in cancer, focal adhesion, and protein digestion and absorption. There were nine hub genes (CDKN3, MKI67, CEP55, SPAG5, AURKA, TOP2A, UBE2C, CHEK1 and BIRC5) identified by PPI and module analysis. In GEPIA database, the expression levels of these genes in lung cancer tissues were significantly upregulated compared with normal lung tissues. The results of prognostic analysis showed that relatively higher expression of hub genes was associated with poor prognosis of lung cancer. In HPA database, most hub genes were highly expressed in lung cancer tissues. The hub genes have good diagnostic efficiency in lung cancer and normal tissues. The expression of any hub gene was associated with the infiltration of at least two immune cells. qRT-PCR confirmed that the expression level of CDKN3, MKI67, CEP55, SPAG5, AURKA, TOP2A were highly expressed in lung cancer tissues. CONCLUSIONS: The hub genes and functional pathways identified in this study may contribute to understand the molecular mechanisms of lung cancer. Our findings may provide new therapeutic targets for lung cancer patients.

Current Research on Pro-drug Therapies for Parkinson's and Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) and Parkinson's (PD) disease are common neurodegenerative conditions of the Central Nervous System (CNS). Thus, these diseases have only been treated symptomatically since no approved drug is available that provides a complete cure. OBJECTIVES: Through reading relevant literatures published at home and abroad, the method and significance of prodrug strategy to increase the efficacy of ad and pd drugs were discussed. METHODS: The biological mechanisms and currently approved drugs for both diseases have been discussed, revealing that most of these treatments utilized existing prodrug design strategies, including increased lipophilicity, and the use of transporters mediation and bio-oxidation to improve oral bioavailability and brain permeability. RESULTS: The purpose of this paper is to review the research progress in the treatment of Neurodegenerative Diseases (NDDS), especially ad and pd, using the prodrug strategy. The research of drug bioavailability and the prodrug strategy of cns targeted drug delivery lay the foundation for drug development to treat these diseases. CONCLUSION: The use of prodrug strategies provides important opportunities for the development of novel therapies for ad and pd.

Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates.

Human sirtuin 5 (SIRT5) plays pivotal roles in metabolic pathways and other biological processes, and is involved in several human diseases including cancer. Development of new potent and selective SIRT5 inhibitors is currently desirable to provide potential therapeutics for related diseases. Herein, we report a series of new 3-thioureidopropanoic acid derivatives, which were designed to mimic the binding features of SIRT5 glutaryl-lysine substrates. Structure-activity relationship studies revealed several compounds with low micromolar inhibitory activities to SIRT5. Computational and biochemical studies indicated that these compounds exhibited competitive SIRT5 inhibition with respect to the glutaryl-lysine substrate rather than nicotinamide adenine dinucleotide cofactor. Moreover, they showed high selectivity for SIRT5 over SIRT1-3 and 6 and could stabilize SIRT5 proteins as revealed by thermal shift analyses. This work provides an effective substrate-mimicking strategy for future inhibitor design, and offers new inhibitors to investigate their therapeutic potentials in SIRT5-associated disease models.

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease.

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 µM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.

Synthesis of osthol-based botanical fungicides and their antifungal application in crop protection.

Plant pathogenic fungi decrease the quality and productivity of plant production. The botanical fungicides have better biocompatibility and rapid biodegradation, little or no cross resistance, and the structural diversity, and thus are beneficial to deal with plant fungal diseases. Osthole has been widely used as the commercial botanical fungicide against powdery mildew in China. In this article, a series of osthole derivatives were synthesized, which respectively contain different substituents on the benzene ring, at the C8-position and pyrone ring. All the target compounds were evaluated in vitro for their antifungal activity against resistant phytopathogenic fungi. Colletotrichum fragariae, Strawberry Botrytis Cinerea, Kiwifruit Botrytis Cinerea, Kiwifruit brown Rots, which are common in fruit fungal diseases. The compound C4 was identified as the most promising candidate with the EC50 values at 38.7 µg/mL against Colletotrichum Fragariae, 14.5 µg/mL against Strawberry Botrytis Cinerea and 24.3 µg/mL against Kiwifruit Botrytis Cinerea, respectively, whereas the antifungal activity against resistant phytopathogenic fungi. of osthole is too low to be used (EC50 > 400 ppm). The results of mycelial relative conductivity determination, PI uptake and fluorescence spectroscopy indicated that the cell membrane of fungi is the key action site of C4. Besides, C4 has the potent inhibitory activity against both of plant and human pathogenic bacteria. Our studies showed that C4 was worthy for further attention as a promising botanical fungicide candidate in crop protection.

Synthesis, biological activities and docking studies of pleuromutilin derivatives with piperazinyl urea linkage.

Antibiotics resistance is becoming increasingly common, involving almost all antibiotics on the market. Diseases caused by drug resistant bacteria, such as MRSA, have high mortality and negatively affect public health. The development of new drugs would be an effective means of solving this problem. Modifications based on bioactive natural products could greatly shorten drug development time and improve success rate. Pleuromutilin, a natural product from the basidiomycete bacterial species, is a promising antibiotic candidate. In this study, a series of novel pleuromutilin derivatives possessing piperazinyl urea linkage were efficiently synthesised, and their antibacterial activities and bactericidal properties were evaluated via MIC, MBC and Time-kill kinetics assays. The results showed that all compounds exhibited potent activities against tested strains, especially MRSA strains with MIC values as low as 0.125 µg/mL; 8 times lower than that of marketed antibiotic Tiamulin. Docking studies indicate substituted piperazinyl urea derivatives could provide hydrogen bonds and initiate π-π stacking between molecules and surrounding residues.