Fetal overgrowth and weight trajectories during infancy and adiposity in early childhood.

BACKGROUND: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood. Little is known about how infancy growth trajectories affect adiposity in early childhood in LGA. METHODS: In the Shanghai Birth Cohort, we followed up 259 LGA (birth weight >90th percentile) and 1673 appropriate-for-gestational age (AGA, 10th-90th percentiles) children on body composition (by InBody 770) at age 4 years. Adiposity outcomes include body fat mass (BFM), percent body fat (PBF), body mass index (BMI), overweight/obesity, and high adiposity (PBF >85th percentile). RESULTS: Three weight growth trajectories (low, mid, and high) during infancy (0-2 years) were identified in AGA and LGA subjects separately. BFM, PBF and BMI were progressively higher from low- to mid-to high-growth trajectories in both AGA and LGA children. Compared to the mid-growth trajectory, the high-growth trajectory was associated with greater increases in BFM and the odds of overweight/obesity or high adiposity in LGA than in AGA children (tests for interactions, all P < 0.05). CONCLUSIONS: Weight trajectories during infancy affect adiposity in early childhood regardless of LGA or not. The study is the first to demonstrate that high-growth weight trajectory during infancy has a greater impact on adiposity in early childhood in LGA than in AGA subjects. IMPACT: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood, but little is known about how weight trajectories during infancy affect adiposity during early childhood in LGA subjects. The study is the first to demonstrate a greater impact of high-growth weight trajectory during infancy (0-2 years) on adiposity in early childhood (at age 4 years) in subjects with fetal overgrowth (LGA) than in those with normal birth size (appropriate-for-gestational age). Weight trajectory monitoring may be a valuable tool in identifying high-risk LGA children for close follow-ups and interventions to decrease the risk of obesity.

Cord blood fatty acid binding protein 4 and lipids in infants born small- or large-for-gestational-age.

Aim: Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. Methods: In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Results: Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. Conclusion: FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.

Docosahexaenoic acid supplementation in gestational diabetes mellitus and neonatal metabolic health biomarkers.

Background and objective: Gestational diabetes mellitus (GDM) "programs" an elevated risk of metabolic dysfunctional disorders in the offspring, and has been associated with elevated leptin and decreased adiponectin levels in cord blood. We sought to assess whether docosahexaenoic acid (DHA) supplementation in GDM affects neonatal metabolic health biomarkers especially leptin and adiponectin. Methods: In a randomized controlled trial, singleton pregnant women with de novo diagnosis of GDM at 24-28 weeks of gestation were randomized to dietary supplementation of 500 mg DHA per day (intervention, n = 30) until delivery or standard care (control, n = 38). The primary outcomes were cord blood leptin and total adiponectin concentrations. Secondary outcomes included high-molecular-weight (HMW) adiponectin and insulin-like growth factor-1 (IGF-1) concentrations in cord blood, maternal glycemic control post-intervention and birth weight (z score). In parallel, 38 euglycemic pregnant women were recruited for comparisons of cord blood biomarkers. Results: There were no significant differences in cord serum leptin, total and HMW adiponectin and IGF-1 concentrations between DHA supplementation and control groups (all p > 0.05). Maternal fasting and 2-h postprandial blood glucose levels at 12-16 weeks post-intervention were similar between the two groups. The newborns in the DHA group had higher birth weight z scores (p = 0.02). Cord blood total and HMW adiponectin concentrations were significantly lower in GDM vs. euglycemic pregnancies. Conclusion: Docosahexaenoic acid supplementation at 500 mg/day in GDM women did not affect neonatal metabolic biomarkers including leptin, adiponectin and IGF-1. The results are reassuring in light of the absence of influence on neonatal adipokines (leptin and adiponectin), and potential benefits to fetal growth and development. Clinical Trial Registration: Clinicaltrials.gov, NCT03569501.

Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors.

BACKGROUND: Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors. RESULTS: Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not. CONCLUSIONS: Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.

[Main Factors Influencing the Platelet Spreading].

OBJECTIVE: To explore the main factors of platelet spreading and provide the foundation for related research. METHODS: Platelets (2×107/ml) were draw from C57BL/6J mouse and kept at 22 ℃ for 1-2 hours. Platelets (2×107/ml) were were allowed to adhere and spread on the fibrinogen-coated slides, after staining F-actin in platelets, the platelets were observed with the confocal microscopy. The effects of different concentrations of fibrinogen (10 µg/ml, 30 µg/ml, 100 µg/ml) and kinds of agonists ï¼»thrombin(0.01,0.05,0.1 U/ml), ADP（5,10,20 µmol/L）, U46619（0.125,0.25,0.5 µmol/L）］ on platelets were analyzed. The platelet spreading was successful if the spreading rate was higher after treated with agonists. RESULTS: Compared to the group which coated with 10 µg/ml and 100 µg/ml fibrinogen, the platelet density is optimal when coated with 30 µg/ml fibrinogen. In addition, under the stimulation of thrombin, ADP and U46619, the spreading rate of platelets showed a certain concentration-dependent increasing. CONCLUSION: The platelet spreading is easily influenced by various factors, the platelet spreading can be induced successfully at 0.1 U/ml thrombin, 20 µmol/L ADP and 0.5 µmol/L U46619 on the slide coated with 30 µg/ml fibrinogen.

Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood.

Gestational diabetes mellitus (GDM) "program" an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.

Sex Dimorphic Associations of Gestational Diabetes Mellitus With Cord Plasma Fatty Acid Binding Protein 4 and Estradiol.

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

[The Role of Zyxin in Regulating Platelet Cytoskeleton Distribution].

OBJECTIVE: To investigate the regulatory effect of zyxin on the distribution of platelet cytoskeleton. METHODS: Platelets were isolated from zyxin-knockout (Zyx-/-) and wild type (WT) mice respectively and corresponding platelet cytoskeleton components were separated. The expressions of ß-actin, α-actinin, filamin A and myosin ⅡA in cytoskeleton components were detected by Western blot. Actin polymerization was induced by the actin polymerization inducer Jasplakinolide (Jas) in WT and Zyx-/- platelets. Also, the expressions of the cytoskeleton proteins in cytoskeleton components were detected by Western blot. WT and Zyx-/- platelets were allowed to spread on fibrinogen-coated surface. Platelet F-actin was labeled with Alexa Fluor 488-conjugated phalloidin and the fluorescent intensity was compared between WT and Zyx-/- platelets. RESULTS: After zyxin gene was knockout, the expressions of cytoskeleton proteins ß-actin, α-actinin, filamin A, and myosin Ⅱ A in resting and Jas-induced platelets were significantly increased. In the platelet spreading on fibrinogen surface, F-actin was increased in Zyx-/- platelets as compared with that in WT platelets. CONCLUSION: Zyxin significantly regulates the distribution of platelet cytoskeleton, which plays an important role in maintaining platelet cytoskeleton homeostasis.

Fibroblast Growth Factor 19 in Gestational Diabetes Mellitus and Fetal Growth.

Fibroblast growth factor 19 (FGF19) has been implicated in glucose homeostasis. Gestational diabetes mellitus (GDM) enhances fetal insulin secretion and fetal growth. Girls weigh less and are more insulin resistant than boys at birth. We sought to assess whether FGF19 is associated with GDM and fetal growth and explore potential sex dimorphic associations. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns of GDM versus euglycemic mothers matched by infant's sex and gestational age at birth. Cord plasma FGF19, insulin, C-peptide, proinsulin, IGF-I and IGF-II concentrations were measured. Cord plasma FGF19 concentrations were similar in GDM versus euglycemic pregnancies (mean ± SD: 43.5 ± 28.2 versus 44.5 ± 30.2 pg/mL, P=0.38). FGF19 was not correlated with IGF-I or IGF-II. FGF19 concentrations were positively correlated with birth weight (r=0.23, P=0.01) and length (r=0.21, P=0.02) z scores, C-peptide (r=0.27, P=0.002) and proinsulin (r=0.27, P=0.002) concentrations in females. Each SD increment in cord plasma FGF19 was associated with a 0.25 (0.07-0.43) increase in birth weight z score in females. In contrast, FGF19 was not correlated with birth weight or length in males. These sex dimorphic associations remained after adjusting for maternal and neonatal characteristics. The study is the first to demonstrate that GDM does not matter for cord blood FGF19 concentrations. The female specific positive correlation between FGF19 and birth weight is suggestive of a sex-dimorphic role of FGF19 in fetal growth. The observations call for more studies to validate the novel findings and elucidate the underlying mechanisms.

Fetuin-A in Infants Born Small- or Large-for-Gestational-Age.

Fetuin-A is a multifunctional glycoprotein that has been implicated in insulin resistance and bone metabolism. We assessed whether fetuin-A is associated with poor or excessive fetal growth. In the Shanghai Birth Cohort, we conducted a nested case-control study of 60 trios of small-for-gestational-age (SGA, birth weight <10th percentile), optimal-for-gestational-age (OGA, 25-75th, the reference) and large-for-gestational-age (LGA, >90th percentile) infants matched by sex and gestational age. Cord plasma concentrations of fetuin-A and fetal growth factors [insulin, proinsulin, insulin-like growth factor (IGF)-I and IGF-II] were measured. Cord plasma fetuin-A concentrations were higher in SGA (809.4 ± 306.9 µg/ml, P = 0.026) and LGA (924.2 ± 375.9 µg/ml, P < 0.001) relative to OGA (680.7 ± 262.1 µg/ml) newborns, and were not correlated to insulin, proinsulin, IGF-I and IGF-II (all P > 0.2). Higher fetuin-A concentrations were associated with increased risks of SGA [OR = 1.67 (1.08-2.58) per SD increment, P = 0.024] and LGA [OR = 2.36 (1.53-3.66), P < 0.001]. Adjusting for maternal and neonatal characteristics and fetal growth factors, the elevated risk changed little for LGA [adjusted OR = 2.28 (1.29-4.01), P = 0.005], but became non-significant for SGA (P = 0.202). Our study is the first to demonstrate that fetuin-A may be involved in excessive fetal growth. This association is independent of fetal growth factors.

Sex dimorphism in the associations of gestational diabetes with cord blood adiponectin and retinol-binding protein 4.

INTRODUCTION: Gestational diabetes (GD) is associated with impaired insulin sensitivity in newborns. Adiponectin and retinol-binding protein 4 (RBP-4) are involved in regulating insulin sensitivity. Females are more likely to develop diabetes at young ages than males. We tested the hypothesis that GD may affect RBP-4 and adiponectin levels in early life, and there may be sex-dimorphic associations. RESEARCH DESIGN AND METHODS: In a nested case-control study of 153 matched pairs of neonates of mothers with GD and euglycemic pregnancies in the Shanghai Birth Cohort, we evaluated cord plasma leptin, high molecular weight (HMW) and total adiponectin and RBP-4 concentrations. RESULTS: Comparing GD versus euglycemic pregnancies adjusted for maternal and neonatal characteristics in female newborns, cord plasma total adiponectin (mean±SD: 30.8±14.3 vs 37.1±16.1 µg/mL, p=0.048) and HMW adiponectin (14.6±7.7 vs 19.3±8.3 µg/mL, p=0.004) concentrations were lower, while RBP-4 concentrations were higher (21.7±5.4 vs 20.0±4.8 µg/mL, p=0.007). In contrast, there were no differences in male newborns (all p>0.2). RBP-4 concentrations were higher in female versus male newborns (21.7±5.4 vs 18.8±4.5 µg/mL, p<0.001) in GD pregnancies only. HMW adiponectin concentrations were significantly higher in female versus male newborns in euglycemic pregnancies only (19.3±8.3 vs 16.1±7.4 µg/mL, p=0.014). CONCLUSIONS: GD was associated with lower cord plasma HMW adiponectin and higher RBP-4 concentrations in female newborns only. The study is the first to reveal a sex-dimorphic early life impact of GD on metabolic health biomarkers in the offspring. GD may alter the normal presence (HMW adiponectin) or absence (RBP-4) of sex dimorphism in some insulin sensitivity regulation-relevant adipokines in early life.

Fetuin-A and fetal growth in gestational diabetes mellitus.

OBJECTIVE: Fetuin-A is a glycoprotein produced by hepatocytes and has been associated with insulin resistance and bone growth in postnatal life. Gestational diabetes mellitus (GDM) is a condition characterized by insulin resistance. It is unclear whether GDM may affect cord blood fetuin-A levels and whether fetuin-A is associated with fetal growth. RESEARCH DESIGN AND METHODS: In a nested case-control study of 153 matched pairs of neonates of mothers with GDM and euglycemic pregnancies in the Shanghai Birth Cohort, we evaluated cord blood fetuin-A in association with GDM and fetal growth. RESULTS: Comparing the newborns of GDM versus euglycemic mothers, cord blood fetuin-A concentrations were similar (mean±SD: 783.6±320.0 vs 754.8±281.9 µg/mL, p=0.53), while insulin-like growth factor (IGF)-I (76.6±27.8 ng/mL vs 68.1±25.1 ng/mL, p=0.008) and IGF-II (195.3±32.5 ng/mL vs 187.5±30.8 ng/mL, p=0.042) concentrations were higher. Cord blood fetuin-A was not correlated with insulin, IGF-I or IGF-II. Cord blood fetuin-A was negatively correlated with birth weight (r=-0.19, p=0.025) and birth length (r=-0.24, p=0.005) z scores in GDM pregnancies, while there were no significant correlations in euglycemic pregnancies (tests for interaction: p=0.014 for birth length, p=0.013 for birth length). Adjusting for maternal and neonatal characteristics, the differential associations remained. CONCLUSIONS: GDM was not associated with cord blood fetuin-A levels. Fetuin-A was negatively associated with fetal growth in GDM but not in euglycemic pregnancies. This novel observation suggests a GDM-conditional negative correlation of fetuin-A with fetal growth.

Retinol-binding protein 4, fetal overgrowth and fetal growth factors.

BACKGROUND: Retinol-binding protein 4 (RBP-4) is an adipokine involved in regulating insulin sensitivity which would affect fetal growth. It is unclear whether RBP-4 is associated with fetal overgrowth, and unexplored which fetal growth factor(s) may mediate the association. METHODS: In the Shanghai Birth Cohort, we studied 125 pairs of larger-for-gestational-age (LGA, birth weight >90th percentile, an indicator of fetal overgrowth) and optimal-for-gestational-age (OGA, 25-75th percentiles) control infants matched by sex and gestational age. We measured cord blood concentrations of RBP-4, insulin, proinsulin, insulin-like growth factor-I (IGF-I), and IGF-II. RESULTS: Cord blood RBP-4 concentrations were elevated in LGA vs. OGA infants (21.9 ± 6.2 vs. 20.2 ± 5.1 µg/ml, P = 0.011), and positively correlated with birth weight z score (r = 0.19, P = 0.003), cord blood proinsulin (r = 0.21, P < 0.001), IGF-I (r = 0.24, P < 0.001), and IGF-II (r = 0.15, P = 0.016). Adjusting for maternal and neonatal characteristics, each SD increment in cord blood RBP-4 was associated with a 0.28 (0.12-0.45) increase in birth weight z score (P < 0.001). Mediation analyses showed that IGF-I could account for 31.7% of the variation in birth weight z score in association with RBP-4 (P = 0.01), while IGF-II was not an effect mediator. CONCLUSIONS: RBP-4 was positively associated with fetal overgrowth. IGF-I (but not IGF-II) may mediate this association.

Placental 11ß-HSD2 and Cardiometabolic Health Indicators in Infancy.

OBJECTIVE: Fetal excessive exposure to glucocorticoids may program cardiometabolic risk. Placental 11 ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) serves as a barrier to prevent fetal overexposure to maternal glucocorticoids. It has not been explored whether placental 11ß-HSD2 levels are associated with cardiometabolic health in postnatal life. RESEARCH DESIGN AND METHODS: In a prospective birth cohort study of 246 mother-infant pairs, we measured placental 11ß-HSD2 expression and maternal (32-35 weeks of gestation) and cord plasma cortisol concentrations. The primary outcomes were HOMA of insulin resistance (IR) and blood pressure (BP) in infants at age 1 year. Other outcomes included fasting insulin, HOMA ß-cell function, carotid intima-media thickness, weight z score, and skinfold thickness (triceps and subscapular) at age 1 year. RESULTS: Placental 11ß-HSD2 expression was negatively correlated with HOMA-IR (r = -0.17, P = 0.021) and fasting insulin (r = -0.18, P = 0.017) and marginally negatively correlated with systolic BP (r = -0.16, P = 0.057) but was not correlated with HOMA of ß-cell function, diastolic BP, carotid intima-media thickness, and skinfold thickness (all P > 0.1) in infants at age 1 year. Cord plasma cortisol was negatively correlated to skinfold thickness (r = -0.20, P = 0007) but was not correlated with other outcomes at age 1 year. Maternal plasma cortisol was positively correlated with maximal carotid intima-media thickness (r = 0.20, P = 0.03) but was not correlated with other outcomes. Adjusting for maternal and infant characteristics, the associations were similar. CONCLUSIONS: The study is the first to show that higher placental 11ß-HSD2 expression is associated with lower IR in infancy. Independent cohort studies are required to confirm this novel finding.

Palladium-Catalyzed Ring-Forming Alkene Aminoaroylation of Unsaturated Hydrazones and Sulfonamides.

The first example of a Pd(OAc)2-catalyzed ring-forming alkene aminoaroylation of unsaturated hydrazones and sulfonamides is described. This protocol features the use of diaryliodonium salts as both oxidants and aryl sources, thus enabling mild reaction conditions, good chemoselectivity, a broad substrate scope, and high functional group tolerance. A wide range of synthetically and biologically important functionalized dihydropyrazoles and isoxazolidines have been obtained in good yields.

A Visible-Light-Driven Iminyl Radical-Mediated C-C Single Bond Cleavage/Radical Addition Cascade of Oxime Esters.

A room-temperature, visible-light-driven N-centered iminyl radical-mediated and redox-neutral C-C single bond cleavage/radical addition cascade reaction of oxime esters and unsaturated systems has been accomplished. The strategy tolerates a wide range of O-acyl oximes and unsaturated systems, such as alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective formation of various chemical bonds. This method thus provides an efficient approach to various diversely substituted cyano-containing alkenes, ketones, carbocycles, and heterocycles.

Synthesis of Dihydropyrazoles via Ligand-Free Pd-Catalyzed Alkene Aminoarylation of Unsaturated Hydrazones with Diaryliodonium Salts.

A ligand-free, palladium-catalyzed aminoarylation reaction of the unactivated alkenes in ß,γ-unsaturated hydrazones is described. This protocol enables efficient and simultaneous formation of C(sp3)-N and C(sp3)-C(sp2) bonds under mild conditions, providing a practical and general approach to various diversely substituted dihydropyrazoles in generally good yields, without the use of any stoichiometric external oxidant.

A visible-light photocatalytic N-radical cascade of hydrazones for the synthesis of dihydropyrazole-fused benzosultams.

An efficient visible light photocatalytic and external oxidant-free N-radical 5-exo cyclization/addition/aromatization cascade of ß,γ-unsaturated hydrazones is described, which provides a practical route to various biologically interesting dihydropyrazole-fused benzosultams in satisfactory yields.