Efficacy and safety of tralokinumab in the treatment of atopic dermatitis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To assess the efficacy and safety of Tralokinumab in the treatment of moderate-to-severe atopic dermatitis (AD). METHODS: PubMed, Embase, Clinical Trials Website, and Cochrane Library were systematically searched for eligible randomized controlled trials which assessed the effects of Tralokinumab on AD. Primary outcomes included Scoring Atopic Dermatitis score, EASI-75%, and Investigator's Global Assessment score of 0 or 1 in 12 to 16 weeks. Secondary outcomes included the Eczema area and severity index score, the Numeric Rating Scales score, the dermatology life quality index score, and the overall incidence of adverse events. The quality of included studies was evaluated using the Cochrane System and the modified Jadad scale. Analysis was performed using Stata 16 software. RESULTS: Eight randomized controlled trials involving 2878 patients were included in this meta-analysis. Compared to placebo, Tralokinumab treatment exhibited a significantly higher Scoring Atopic Dermatitis score [SMD = -0.53, 95% confidence intervals [CI]: -0.62 to -0.44, P < .00001], an increased number of patients with EASI-75% [odds ratio (OR) = 2.44, 95% CI: 2.00-2.97, P < .00001] and Investigator's Global Assessment score of 0 or 1 in 12 to 16 weeks [OR = 2.12, 95% CI: 1.71-2.63, P < .00001]. No significant difference was observed in the incidence of overall adverse events [OR = 1.00, 95% CI: 0.85-1.18, P = 1.00] between the 2 groups. CONCLUSION: Tralokinumab is effective and safe in treatment of moderate-to-severe AD.

Hypsochromic Shift Donor-Acceptor NIR-II Dye for High-Efficiency Tumor Imaging.

Nowadays, second near-infrared window (NIR-II) dyes' development focuses on pursuing a longer absorption/emission wavelength and higher quantum yield, which usually means an extended π conjugation system, resulting in an enormous molecular weight and poor druggability. Most researchers thought that the reduced π conjugation system would bring on a blueshift spectrum that causes dim imaging qualities. Little efforts have been made to study smaller NIR-II dyes with a reduced π conjugation system. Herein, we synthesized a reduced π conjugation system donor-acceptor (D-A) probe TQ-1006 (Em = 1006 nm). Compared with its counterpart donor-acceptor-donor (D-A-D) structure TQT-1048 (Em = 1048 nm), TQ-1006 exhibited comparable excellent blood vessels, lymphatic drainage imaging performance, and a higher tumor-to-normal tissue (T/N) ratio. An RGD conjugated probe TQ-RGD showed an extra high contrast tumor imaging (T/N ≥ 10), further proving D-A dyes' excellent NIR-II biomedical imaging applications. Overall, the D-A framework provides a promising approach to designing next-generation NIR-II fluorophores.

Design, Synthesis, and Antitumor Activities of Isomers of Artemisinin Dimer Derivatives.

In recent years, numerous studies have reported on the anti-tumor properties of artemisinin and its derivatives. However, the relationship between their artemisinin chirality and activity remains unknown. In this study, we synthesized a series of artemisinin dimer derivatives with three different chiral structures and tested their antiproliferative activity in MCF-7 and HepG2 cells using the CCK-8 assay. Interestingly, we discovered that artemisinin dimer derivatives with ß, ß and α, ß conformations at C-10 exhibited stronger anti-tumor activity than those with an α, α configuration in MCF-7 and HepG2 cells. Notably, compound 4 showed an activity of 0.06 µM in MCF-7 cells. This study demonstrates the relationship between the conformation and activity of artemisinin dimer derivatives, and these derivatives have the potential to be developed into anti-cancer drugs.

ROS-activatable nanocomposites for CT imaging tracking and antioxidative protection of mesenchymal stem cells in idiopathic pulmonary fibrosis therapy.

Mesenchymal stem cell (MSC) transplantation is emerging as a promising approach in the treatment of idiopathic pulmonary fibrosis (IPF), while it is still impeded by several challenges, including unsatisfactory treatment outcomes due to the poor survival of transplanted MSCs, and the lack of non-invasive and long-term imaging modality for tracking the behavior of MSCs. Herein, copper-based nanozyme (CuxO NPs) and gold nanoparticles (Au NPs) were encapsulated in oxidation-sensitive dextran (Oxi-Dex), a dextran derivative with reactive oxygen species (ROS)-responsiveness, forming a kind of novel nanocomposites (assigned as RSNPs) to act as ROS scavengers and computer tomography (CT) imaging tracers. After being internalized by MSCs, RSNPs enabled continuous CT imaging tracking of the transplanted MSCs for 21 days in IPF treatment, obtaining the location and distribution of the transplanted MSCs. Once MSCs were attacked by oxidative stress, the intracellular RSNPs could activate ROS clearance on demand by releasing CuxO NPs, thereby enhancing the therapeutic efficacy against IPF by improving cell survival. Taken together, a novel multifunctional RSNP was fabricated to label MSCs for CT imaging tracking and clearing superfluous ROS, presenting a promising high-efficient IPF therapy.

Public Data Set of Protein-Ligand Dissociation Kinetic Constants for Quantitative Structure-Kinetics Relationship Studies.

Protein-ligand binding affinity reflects the equilibrium thermodynamics of the protein-ligand binding process. Binding/unbinding kinetics is the other side of the coin. Computational models for interpreting the quantitative structure-kinetics relationship (QSKR) aim at predicting protein-ligand binding/unbinding kinetics based on protein structure, ligand structure, or their complex structure, which in principle can provide a more rational basis for structure-based drug design. Thus far, most of the public data sets used for deriving such QSKR models are rather limited in sample size and structural diversity. To tackle this problem, we have compiled a set of 680 protein-ligand complexes with experimental dissociation rate constants (k off), which were mainly curated from the references accumulated for updating our PDBbind database. Three-dimensional structure of each protein-ligand complex in this data set was either retrieved from the Protein Data Bank or carefully modeled based on a proper template. The entire data set covers 155 types of protein, with their dissociation kinetic constants (k off) spanning nearly 10 orders of magnitude. To the best of our knowledge, this data set is the largest of its kind reported publicly. Utilizing this data set, we derived a random forest (RF) model based on protein-ligand atom pair descriptors for predicting k off values. We also demonstrated that utilizing modeled structures as additional training samples will benefit the model performance. The RF model with mixed structures can serve as a baseline for testifying other more sophisticated QSKR models. The whole data set, namely, PDBbind-koff-2020, is available for free download at our PDBbind-CN web site (http://www.pdbbind.org.cn/download.php).

Circulating microRNAs Are Associated With Metabolic Markers in Adolescents With Hepatosteatosis.

Background: Altered hepatic microRNA (miRNA) expression may play a role in the development of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Circulating miRNAs could mirror the liver metabolism. Objective: This study aimed to assess the relationship between serum miRNA profile in children with obesity, IR, and NAFLD. Methods: Adolescents with obesity (n = 31) were stratified based on insulin resistance and NAFLD status. One-hundred seventy-nine miRNAs were determined in the serum by quantitative RT-PCR. Differentially expressed miRNAs were compared between groups, and log-transformed levels correlated with metabolic markers and intrahepatic triglyceride. Results: Serum miR-21-5p, -22-3p, -150-5p, and -155-5p levels were higher in children with IR and NAFLD, and their expression levels correlated with hepatic fat and serum triglyceride. In patients with NAFLD, miR-155-5p correlated with ALT (r = 0.68, p<0.01) and AST (r = 0.64, p<0.01) and miR-21-5p and -22-3p levels correlated with plasma adiponectin (r = -0.71 and r = -0.75, respectively, p<0.05) and fibroblast growth factor-21 (r = -0.73 and r = -0.89, respectively, p<0.01). miR-27-3a level was higher in children without IR and NAFLD. Conclusions: Several miRNAs are differentially expressed in children with IR and NAFLD. Determining their mechanistic roles may provide newer diagnostic tools and therapeutic targets for pediatric NAFLD.

Synthesis and BK channel-opening activity of 2-amino-1,3-thiazole derivatives.

A series of 2-amino-5-arylmethyl- or 5-heteroarylmethyl-1,3-thiazole derivatives were synthesized and evaluated for BK channel-opening activities in cell-based fluorescence assay and electrophysiological recording. The assay results indicated that the activities of the investigated compounds were influenced by the physicochemical properties of the substituent at benzene ring.

Aberrant activation of the complement system in renal grafts is mediated by cold storage.

Aberrant complement activation leads to tissue damage during kidney transplantation, and it is recognized as an important target for therapeutic intervention. However, it is not clear whether cold storage (CS) triggers the complement pathway in transplanted kidneys. The goal of the present study was to determine the impact of CS on complement activation in renal transplants. Male Lewis and Fischer rats were used, and donor rat kidneys were exposed to 4 h or 18 h of CS followed by transplantation (CS + transplant). To study CS-induced effects, a group with no CS was included in which the kidney was removed and transplanted back to the same rat [autotransplantation (ATx)]. Complement proteins (C3 and C5b-9) were evaluated with Western blot analysis (reducing and nonreducing conditions) and immunostaining. Western blot analysis of renal extracts or serum indicated that the levels of C3 and C5b-9 increased after CS + transplant compared with ATx. Quite strikingly, intracellular C3 was profoundly elevated within renal tubules after CS + transplant but was absent in sham or ATx groups, which showed only extratubular C3. Similarly, C5b-9 immunofluorescence staining of renal sections showed an increase in C5b-9 deposits in kidneys after CS + transplant. Real-time PCR (SYBR green) showed increased expression of CD11b and CD11c, components of complement receptors 3 and 4, respectively, as well as inflammatory markers such as TNF-α. In addition, recombinant TNF-α significantly increased C3 levels in renal cells. Collectively, these results demonstrate that CS mediates aberrant activation of the complement system in renal grafts following transplantation.NEW & NOTEWORTHY This study highlights cold storage-mediated aberrant activation of complement components in renal allografts following transplantation. Specifically, the results demonstrate, for the first time, that cold storage functions in exacerbation of C5b-9, a terminal cytolytic membrane attack complex, in renal grafts following transplantation. In addition, the results indicated that cold storage induces local C3 biogenesis in renal proximal cells/tubules and that TNF-α promotes C3 biogenesis and activation in renal proximal tubular cells.

Circulating miRNA Signatures Associated with Insulin Resistance in Adolescents with Obesity.

PURPOSE: MicroRNAs (miRNAs) are implicated in metabolic changes accompanying progression of obesity, insulin resistance (IR), and metabolic disorders in children. Identifying circulating miRNAs that uniquely associate with these disorders may be useful in early identification and prevention of obesity-related complications. We aimed to identify circulating miRNA signatures that distinguish adolescents with obesity and IR from those with obesity unaccompanied by IR. METHODS: Adolescents (aged 10-17 years) with obesity were recruited from a weight management clinic. Fasting serum samples were obtained from 33 participants. A total of 179 miRNAs were queried by a quantitative RT-PCR-based miRNA focus panel. Differentially expressed miRNAs were compared between groups using Student's t-test or one-way ANOVA analysis, and the association between IR evaluated by homeostatic model assessment model (HOMA-IR > 4) and body mass index (BMI) status was assessed using Pearson's correlation analysis. RESULTS: We found an expression pattern consisting of 12 elevated miRNAs linked to IR in obese adolescents. miR-30d, -221, and -122 were significantly correlated with clinical and biochemical markers of obesity and IR, suggestive of IR in adolescents at risk. CONCLUSION: Specific signatures of circulating miRNAs reflected metabolic phenotypes and predicted the presence of IR in adolescents with obesity, suggesting that miRNA indicators may identify obesity-associated complications in childhood. Further studies will be needed to understand cause versus effect and the mechanisms by which IR status links to changes in blood miRNA profiles.

Early Infant Formula Feeding Impacts Urinary Metabolite Profile at 3 Months of Age.

There is a growing consensus that nutritional programming may persist and influence risk for several chronic diseases in adulthood. In the present study, we used urinary metabolic analysis in assessing diet effects on early-life metabolism. Urine samples from healthy three-month-old infants fed human milk (HM; n = 93), cow's milk-based infant formula [MF; n = 80], or soy protein-based infant formula (SF; n = 76) were analyzed with an untargeted metabolomics approach using GC-TOF MS. PLS-DA and ANOVA analyses were performed using MetaboAnalyst (v4.0). A total of 150 metabolites differed significantly among the feeding groups, including dietary-specific patterns of urinary metabolites of sugars, sugar alcohols, amino acids, and polyphenols. Urinary metabolites may mirror the infant's overall metabolism and serve as a noninvasive tool to examine the neonatal effects of diet on early-infant metabolism.

Fibroblast Growth Factor-21 to Adiponectin Ratio: A Potential Biomarker to Monitor Liver Fat in Children With Obesity.

Background: There is a pressing need for effective and non-invasive biomarkers to track intrahepatic triglyceride (IHTG) in children at-risk for non-alcoholic fatty liver disease (NAFLD), as standard-of-care reference tools, liver biopsy and magnetic resonance imaging (MRI), are impractical to monitor the course disease. Objective: We aimed to examine the association between serum fibroblast growth factor (FGF)-21 to adiponectin ratio (FAR) and IHTG as assessed by MRI in children with obesity. Methods: Serum FGF21 and adiponectin levels and IHTG were measured at two time points (baseline, 6 months) in obese children enrolled in a clinical weight loss program. The association between percent change in FAR and IHTG at final visit was examined using a multiple linear regression model. Results: At baseline, FAR was higher in the subjects with NAFLD (n = 23, 35.8 ± 41.9 pg/ng) than without NAFLD (n = 35, 19.8 ± 13.7 pg/ng; p = 0.042). Forty-eight subjects completed both visits and were divided into IHTG loss (≥1% reduction than baseline), no change (within ±1% change), and gain (≥1% increase than baseline) groups. At 6 months, the percent change in FAR was different among the three groups (p = 0.005). Multiple linear regression showed a positive relationship between percent change in FAR and the final liver fat percent in sex and pubertal stage-similar subjects with NAFLD at baseline (slope coefficient 6.18, 95% CI 1.90-10.47, P = 0.007), but not in those without NAFLD. Conclusions: Higher value in percent increase in FAR is positively associated with higher level of IHTG percent value at 6 months in children with baseline NAFLD. FAR could be a potential biomarker to monitor the changes in IHTG in children with NAFLD.

Synthesis and biological activity of C-7, C-9 and C-10 modified taxane analogues from 1-deoxybaccatin VI.

A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead compounds for anticancer drug design.

Divergence in aerobic capacity impacts bile acid metabolism in young women.

Liver adaptations may be critical for regular exercise and high aerobic capacity to protect against metabolic disease, but mechanisms remain unknown. Bile acids (BAs) synthesized in the liver are bioactive and can putatively modify energy metabolism. Regular exercise influences BA metabolism in rodents, but effects in humans are unknown. This study tested whether female subjects screened for high aerobic capacity (Hi-Fit, n = 19) [peak oxygen consumption (V̇o2peak) ≥45 mL·kg-1·min-1] have increased hepatic BA synthesis and different circulating BA composition compared with those matched for age and body mass with low aerobic capacity (Lo-Fit, n = 19) (V̇o2peak ≤35 mL·kg-1·min-1). Diet patterns, activity level, stool, and blood were collected at baseline before participants received a 1-wk standardized, eucaloric diet. After the 1-wk standardized diet, stool and blood were again collected and an oral glucose tolerance test (OGTT) was performed to assess insulin sensitivity and postprandial BA response. Contrary to our hypothesis, serum 7α-hydroxy-4-cholesten-3-one (C4), a surrogate of BA synthesis, was not different between groups, whereas Hi-Fit women had lower fecal BA concentrations compared with Lo-Fit women. However, Lo-Fit women had a higher and more sustained rise in circulating conjugated BAs during the OGTT. Hi-Fit women showed a significant post-OGTT elevation of the secondary BA, lithocholic acid (a potent TGR5 agonist), in contrast to Lo-Fit women where no response was observed. A 1-wk control diet eliminated most differences in circulating BA species between groups. Overall, the results emphasize the importance of using a standardized diet when evaluating BAs and indicate that regular exercise and aerobic capacity modulate BA metabolism under postprandial conditions.NEW & NOTEWORTHY Women with contrasting exercise and aerobic capacity levels show clear differences in bile acid (BA) metabolism. Women with low aerobic capacity (Lo-Fit) have increased circulating conjugated BAs post oral glucose tolerance test (OGTT), whereas women with high aerobic capacity (Hi-Fit) display a transient increase. Hi-Fit women show an increase in the secondary BA, lithocholic acid, during the OGTT not seen in Lo-Fit women. Differences in circulating BA species between Hi- and Lo-Fit women possibly contribute to differences in insulin sensitivity and energy regulation via different signaling mechanisms.

MicroRNA profiles were altered in neonatal piglet mammary glands following postnatal infant formula feeding.

Postnatal dietary modulation of microRNAs (miRNAs) and effects on miRNA-mRNA interactions in tissues remain unknown. This study aimed to investigate whether dietary factors (formula vs. breastfeeding) affect mammary miRNA expression and to determine if these changes are concurrent with developmental alterations of the mammary gland in neonatal piglets. Female Yorkshire/Duroc piglets were fed sow's milk or cow's milk- or soy-based infant formula (from postnatal day 2 to day 21; n=6/group). Differentially expressed miRNAs were determined using mammary miRNA profiling, followed by miRNA and mRNA expressions characterized by quantitative reverse-transcription polymerase chain reaction. Milk and soy formulas reduced expressions of miR-1, -128, -133a, -193b, -206 and -27a; miRNA down-regulation altered mRNA expressions of genes (e.g., Ccnd1, Tgfb3, Igf1r and Tbx3) that were consistent with enhanced cell proliferation and suppressed apoptotic processes in the developing mammary gland. Interestingly, down-regulation of miR-1, -128 and -27a also correlated with increased mRNA genes such as Hmgcs and Hmgcr encoding cholesterol synthesis in the mammary glands in response to lower circulating cholesterol levels. Infant formula feeding affected mammary miRNA profiles in neonatal piglets, concurrent with increased expression of cell proliferation and cholesterol synthesis genes, suggesting early nutritional modulation of miRNAs may contribute to regulation of proliferative status and cholesterol homeostasis of developing mammary glands during infancy.

Copper-Catalyzed Oxalamide-Directed ortho-C-H Amination of Anilines with Alkylamines.

A copper-catalyzed oxalamide-directed ortho-C-H amination of anilines has been developed by using 1 atm of air as the sole oxidant. The protocol shows excellent functional group tolerance, and some heterocyclic amines including indole, benzothiophene, benzothiazole, quinoline, isoquinoline, and quinoxaline could be compatible in the reaction. The late-stage diversification of medicinal drugs demonstrates the synthetic utility of this protocol.

Association between non-alcoholic fatty liver disease and myocardial glucose uptake measured by 18F-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has emerged as an independent risk factor for cardiovascular diseases. However, there were few studies evaluating the condition of myocardial glucose metabolism in patients with NAFLD. Therefore, the aim of this study was to investigate the association between NAFLD and myocardial glucose uptake assessed by using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and whether or not alteration of myocardial glucose uptake could be an indicator linking to cardiac dysfunction in NAFLD individuals. METHODS AND RESULTS: A total of 743 asymptomatic subjects (201 with NAFLD, 542 without NAFLD) were retrospectively studied. The ratio of maximum myocardium FDG uptake to the mean standardized uptake value of liver (SUVratio) was calculated to estimate myocardial glucose uptake by using 18F-FDG PET. The diagnosis of fatty liver and fatty liver grading was confirmed by unenhanced CT according to diagnostic criterion of previous studies. The myocardial geometric and functional data were obtained by echocardiogram. Myocardial glucose uptake was significantly lower in individuals with NAFLD compared with those without fatty liver (P < .001). When analysis of association trend was performed, SUVratio quartiles showed correlated inversely and strongly with liver steatosis (P < .001). NAFLD patients with lower myocardial glucose uptake were more likely to have higher proportion of increased LV filling pressure (P < .05). A significant relationship between myocardial SUVratio and E/e' ratio was presented in the trend analysis (P < .05). Moreover, multivariate regression analysis showed that myocardial glucose uptake was independently associated with NAFLD after adjusting for clinical important factors (all P < .001). CONCLUSIONS: The presence of NAFLD in otherwise healthy subjects is closely associated with decreased myocardial glucose uptake assessing by 18F-FDG PET imaging. Furthermore, the NAFLD individuals with lower myocardial glucose uptake are more likely to have high risk of having impaired diastolic heart function.

Design, synthesis of novel C-3'-N-sulfonyl modified taxane analogues from 1-deoxybaccatin VI and their impact on anti-HCC activity.

A new series of C-3'-N-sulfonyl paclitaxel analogs were designed and synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. The synthesized compounds were evaluated for their in vitro anti-Hepatocellular carcinoma (HCC) activity against human hepatoma (HepG2) cell line. Bioassay results showed that compounds 17c, 17d and 17f exhibited more potent inhibitory activity against HepG2 cell line in comparison with paclitaxel. It is suggested that paclitaxel analogs containing the C-3'-N-sulfonyl could be considered as a precursor structure for further synthesis of more potent analogues.

Infant Formula Feeding Changes the Proliferative Status in Piglet Neonatal Mammary Glands Independently of Estrogen Signaling.

BACKGROUND: Soy infant formula contains isoflavones, which are able to bind to and activate estrogen receptor (ER) pathways. The mammary gland is sensitive to estrogens, raising concern that the use of soy formulas may promote premature development. OBJECTIVE: We aimed to determine if soy formula feeding increases mammary gland proliferation and differentiation in comparison to other infant postnatal diets. METHODS: White-Dutch Landrace piglets aged 2 d received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/(kg·d); M + E2), or milk formula supplemented with genistein (84 mg/L of diet; M + G) until day 21. Mammary gland proliferation and differentiation was assessed by histology, and real-time RT-PCR confirmation of differentially expressed genes identified by microarray analysis. RESULTS: Mammary terminal end bud numbers were 19-31% greater in the Milk, Soy, and M + G groups relative to the Sow and M + E2, P <0.05. Microarray analysis identified differentially expressed genes between each formula-fed group relative to the Sow (±1.7-fold, P <0.05). Real-time RT-PCR confirmed 2- to 4-fold increases in mRNA transcripts of genes involved in cell proliferation, insulin-like growth factor 1 (IGF1), fibroblast growth factor 10 (FGF10), and fibroblast growth factor 18 (FGF18), in all groups relative to the Sow, P <0.05. In contrast, genes involved in cell differentiation and ductal morphogenesis, angiotensin II receptor type 2 (AGTR2), microtubule associated protein 1b (MAP1B), and kinesin family member 26b (KIF26B), were significantly upregulated by 2-, 4-, and 13-fold, respectively, in the M + E2 group. Additionally, mRNA expression of ER-specific gene targets, progesterone receptor (PGR), was increased by 12-fold, and amphiregulin (AREG) and Ras-like estrogen regulated growth inhibitor (RERG) expression by 1.5-fold in the M + E2 group, P <0.05. In the soy and M + G groups, mRNA expressions of fatty acid synthesis genes were increased 2- to 4-fold. CONCLUSIONS: Our data indicate soy formula feeding does not promote ER-signaling in the piglet mammary gland. Infant formula feeding (milk- or soy-based) may initiate proliferative pathways independently of estrogenic signaling.

Efficient Synthesis of Spirooxindole Pyrrolones by a Rhodium(III)-Catalyzed C-H Activation/Carbene Insertion/Lossen Rearrangement Sequence.

A rhodium(III)-catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem C-H activation, carbene insertion, Lossen rearrangement, and a nucleophilic addition process. The potential utility of this reaction was further demonstrated by the late-stage diversification of drug molecules.

Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media.

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.