An Enzymatic Carbon-Carbon Bond Cleavage and Aldol Reaction Cascade Converts an Angular Scaffold into the Linear Tetracyclic Core of Ochraceopones.

Meroterpenoids of the ochraceopones family featuring a linear tetracyclic scaffold exhibit exceptional antiviral and anti-inflammatory activities. The biosynthetic pathway and chemical logic to generate this linear tetracycle, however, remain unknown. In this study, we identified and characterized all biosynthetic enzymes to afford ochraceopones and elucidated the complete biosynthetic pathway. We demonstrated that the linear tetracyclic scaffold of ochraceopones was derived from an angular tetracyclic precursor. A multifunctional cytochrome P450 OchH was validated to catalyze the free-radical-initiated carbon-carbon bond cleavage of the angular tetracycle. Then, a new carbon-carbon bond was verified to be constructed using a new aldolase OchL, which catalyzes an intramolecular aldol reaction to form the linear tetracycle. This carbon-carbon bond fragmentation and aldol reaction cascade features an unprecedented strategy for converting a common angular tetracycle to a distinctive linear tetracyclic scaffold in meroterpenoid biosynthesis.

Mutasynthesis Generates Antibacterial Benzothiophenic-Containing Nosiheptide Analogues.

Nosiheptide is a bicyclic thiopeptide featuring an indole-containing side ring, which is biologically important in maintaining its potent antibacterial activity. By using mutational biosynthesis, the pharmaceutically significant benzothiophene was introduced into the nosiheptide biosynthetic pathway, resulting in the generation of three bioactive nosiheptide analogues with characteristic benzothiophene-containing side rings. Insights were provided into the transformation relationship of these analogues, which effectively improves the yield of S-NOS-1 with favorable activity against Gram-positive pathogens.

Nosiheptide analogues as potential antibacterial agents via dehydroalanine region modifications: Semi-synthesis, antimicrobial activity and molecular docking study.

The frequent and inappropriate use of antibiotics aggravate the variation and evolution of multidrug-resistant bacteria, posing a serious threat to public health. Nosiheptide (NOS) has excellent lethality against a variety of Gram-positive bacteria, however the physical and chemical drawbacks hamper its routine application in clinical practice. In this study, by using NOS as the starting material, a total of 15 NOS analogues (2a-4e) were semi-synthesized via its dehydroalanine residue reacting with monosubstituted anilines. In vitro antimicrobial susceptibilities of NOS and its analogues against two methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) clinical isolates were determined by broth microdilution assay to determine the minimum inhibitory concentration (MIC). Antimicrobial susceptibility testing data shown that most of the NOS analogues had a better antibacterial effect than the parent compound, with compound 3c exhibiting the highest antibacterial activity against VRE (MIC = 0.0078 mg/L) and MRSA (MIC < 0.0039 mg/L). Molecular docking of synthetic compounds was also performed to verify the binding interactions of NOS analogues with the target. Our data indicated that compound 3c possesses stronger and more complex intermolecular force than other analogues, which is consistent with the results of the biological activity evaluation. Overall, this study identified a number of potential antibacterial NOS analogues that could act as potent therapeutic agents for multidrug-resistant bacterial infections.

Mutational biosynthesis to generate novel analogs of nosiheptide featuring a fluorinated indolic acid moiety.

Nosiheptide (NOS) is a member of bicyclic thiopeptides possessing a biologically important indolic acid (IA) moiety appended onto the family-characteristic core system. The IA formation relies primarily on NosL, a radical S-adenosylmethionine (SAM) protein that catalyzes a complex rearrangement of the carbon side chain of l-tryptophan, leading to the generation of 3-methyl-2-indolic acid (MIA). Here, we establish an efficient mutational biosynthesis strategy for the structural expansion of the side-ring system of NOS. The nosL-deficient mutant Streptomyces actuosus SL4005 complemented by chemically feeding 6-fluoro-MIA is capable of accumulating two new products. The target product 6'-fluoro-NOS contains an additional fluorine atom at C6 of the IA moiety, in contrast with an unexpected product 6'-fluoro-NOSint that features an open side ring and a bis-dehydroalanine (Dha) tail. The newly obtained 6'-fluoro-NOS displayed equivalent or slightly reduced activities against the tested drug-resistant pathogens compared with NOS, but dramatically decreased water solubility compared with NOS. Our results indicate that the modification of the IA moiety of NOS not only affects its biological activity but also affects its activity which will be key considerations for further modification.

Lipid accumulation product (LAP) was independently associatedwith obstructive sleep apnea in patients with type 2 diabetes mellitus.

BACKGROUND: Lipid accumulation product (LAP) is a new index based on a combination of waist circumference (WC) and serum triglycerides (TG) reflecting lipid accumulation. In this cross-sectional study, we aimed to explore whether LAP was independently associated with obstructive sleep apnea (OSA) in Type 2 diabetes mellitus (T2DM) patients. METHODS: A cross-sectional study of 317 T2DM patients who underwent overnight polysomnography (PSG) tests was conducted. The clinical data between non-OSA group and OSA group were compared. Multivariable linear regression and multivariable logistic regression analyses were performed to determine associations of LAP, with apnea-hypopnea index (AHI) and OSA. RESULTS: Among 317 patients, 219 (69.1%) were men, and the mean ages (±SD) were 51.4 (±13.5) years for men and 54.6 (±15.1) years for women (p = 0.067). The prevalence rates of OSA were 63.0% for men and 68.4% for women (p = 0.357). LAP (log-transformed) was significantly correlated with AHI (log-transformed), with the Pearson's correlation coefficient of 0.170 (p = 0.002). With adjustment for potential confounding factors, multivariate linear regression analyses showed the association of LAP with AHI was not statistically significant, with the adjusted linear regression coefficients (95% CI) of per SD increase of LAP for AHI (log-transformed) was 0.092 (- 0.011-0.194, p = 0.080). Multivariate logistic regression analyses showed LAP was significantly associated with increased risk of OSA, with the adjusted OR (95%CI) of per SD increase of LAP of 1.639 (1.032-2.604, p = 0.036). However, as constituents of LAP, neither TG nor WC was significantly associated with AHI and OSA. CONCLUSION: LAP was independently associated with OSA and might be used as a potential OSA risk marker in T2DM patients, beyond the general index of obesity.

Visible Light-Induced Radical Cyclization of Tertiary Bromides with Isonitriles To Construct Trifluoromethylated Quaternary Carbon Center.

The reaction of trifluoromethylated tertiary bromides with isonitriles induced by visible light is reported. Defluorination was avoided in a radical process. This method provides an efficient approach to compounds containing a trifluoromethylated quaternary carbon center, most of which show excellent potential to be agrochemicals. In addition, the bromides were prepared from perfluoroisobutylene, which is a waste from industry, after several steps. This reaction shows a feasible transfer of harmful waste into useful compounds.

Visible light-promoted difluoromethylthiolation of aryldiazonium salts.

Difluoromethylthiolation of aryldiazonium salts under photocatalytic conditions with a shelf-stable, easily prepared and inexpensive reagent, PhSO2SCF2H was described. A variety of difluoromethylthioethers were obtained utilizing aryldiazonium salts containing different functional groups. Aryldiazonium salts with a heteroarene moiety were tolerated. Fluorescence quenching experiments indicated that both oxidative and reductive quenching cycles occurred during this process.

Enantioselective Pd-catalyzed allylation of acyclic α-fluorinated ketones.

Significant synthetic challenges remain for the asymmetric synthesis of tertiary α-fluoro ketones, which are potentially useful molecules for the development of drugs, agrochemicals, and functional materials. Herein, we describe the development of a method for the catalytic enantioselective synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones. Enantioenriched acyclic α-cabonyl tertiary fluorides can be produced with the aid of a palladium/phosphinooxazoline catalyst.

Copper-Catalyzed, Interrupted Remote Fluoromethylthiolation of Unactivated C(sp3)-H Bonds.

An efficient copper-catalyzed selective fluoromethylthiolation of an inert δ-C(sp3)-H bond in sulfonamides was reported. In the presence of a copper catalyst and PhSO2SRf, the radical generated through 1,5-hydrogen atom transfer (HAT) was sufficiently trapped by PhSO2SRf, instead of copper, which was prevalent in metal-catalyzed radical-relay processes, incorporating a fluoromethylthio group into molecules. The general substrate scope and mild conditions endowed the method with wide potential applications in pharmaceuticals and agrochemicals.

ß-Terrecyclene synthase constructs the quadrane backbone in terrecyclic acid biosynthesis.

Quadrane sesquiterpenes featuring a distinctive tricyclic skeleton exhibit potent antimicrobial and anticancer activities. Although extensive studies have attempted to reveal the multistep carbocation rearrangement involved in the formation of the tricyclic quadrane scaffold, the exact biosynthetic pathway and chemical logic to generate the quadrane structure remains mysterious. Here we identified a novel sesquiterpene synthase that is capable of generating ß-terrecyclene possessing the quadrane scaffold and characterized the biosynthetic pathway of a representative fungal quadrane terrecyclic acid. Further mutagenesis coupled with isotopically sensitive branching studies of this ß-terrecyclene synthase provided insight into the mechanism involved in the formation of the quadrane scaffold.

Risk Factors for Glycemic Control in Hospitalized Patients with Type 2 Diabetes Receiving Continuous Subcutaneous Insulin Infusion Therapy.

INTRODUCTION: Patients with diabetes are confronted with numerous obstacles to achieve adequate glycemic control during hospitalization. The aim of this study was to explore the risk factors associated with glycemic control in hospitalized patients with type 2 diabetes mellitus (T2DM) treated with continuous subcutaneous insulin infusion (CSII). METHODS: This cross-sectional study included 5223 patients hospitalized with T2DM in a tertiary hospital in Xiamen (China) between January 2017 and December 2019. All patients were managed according to established protocols for glycemic monitoring and insulin pump treatment regimens. Demographic information and clinical profiles were collected from electronic health records. Multiple linear regression analysis was used to identify the risk factors associated with glycemic control. RESULTS: Among the 5223 hospitalized patients with T2DM receiving CSII therapy, 55.2% achieved their ideal blood glucose level (3.9-10.0 mmol/L), 44.5% experienced hyperglycemia (> 10.0 mmol/L), and 0.3% experienced hypoglycemia (< 3.9 mmol/L) during their hospitalization. Multivariate analyses showed that among inpatients with T2DM, older age, male gender, higher low-density lipoprotein-cholesterol (LDL-C) level, lower C-peptide (C-P) level, lower body mass index (BMI), longer duration of diabetes, previous insulin prescriptions, nephropathy, and retinopathy were factors more likely to be associated with a blood glucose level in the hyperglycemic range (P < 0.05). We also observed that among hospitalized patients with T2DM, those with lower BMI, lower C-P, lower LDL-C, longer disease duration, and previous insulin prescriptions were more likely to correlate with a higher proportion of hypoglycemia range (all P < 0.05). CONCLUSION: Older age, male gender, lower BMI, lower C-P, higher LDL-C, previous insulin prescriptions, longer duration of diabetes, nephropathy, and retinopathy may be risk factors for a higher proportion of hyperglycemic events in hospitalized patients with T2DM under CSII therapy. Furthermore, lower BMI, lower C-P, lower LDL-C, longer duration of diabetes, and previous insulin prescriptions were found to be important factors for a higher proportion of hypoglycemic events. Evaluating the clinical features, comorbidities, and complications of hospitalized patients is essential to achieve reasonable glycemic control.

Visceral Adipose Tissue Indices Independently Correlated with Obstructive Sleep Apnea in Patients with Type 2 Diabetes.

AIMS: We aimed to explore whether visceral adiposity indices were significantly associated with obstructive sleep apnea (OSA) in type 2 diabetes (T2DM) patients. METHODS: 100 patients with T2DM who underwent overnight polysomnography were analyzed in this study. Anthropometric data, lipid profiles, and glycemic parameters were recorded. Body fat percentage (BFP) and visceral adipose tissue area (VAT area) were collected from a whole body scan using dual-energy X-ray absorptiometry (DXA). Multivariate logistic regression analysis was performed to explore the associations of AHI with BFP, VAT area, and CVAI. RESULTS: The prevalence rate of OSA was 80%, and the mean (±SD) of age was 47.0 ± 13.6 years. Apnea-hypopnea index (AHI) was significantly and positively associated with either VAT area (r = 0.433, p ≤ 0.001) or Chinese visceral adiposity index (CVAI) (r = 0.355, p ≤ 0.001) but not for BFP (r = 0.107, p = 0.294). Multivariate logistic regression analyses showed that VAT area and CVAI were significantly associated with increased risk of OSA, and the adjusted ORs were (95% CI) 1.025 (1.003-1.047, p = 0.023) and 1.018 (1.002-1.034, p = 0.030), respectively. However, there was no significant association between BFP and increased risk of OSA. CONCLUSIONS: VAT area and CVAI were independent risk factors of OSA in the patients with T2DM.

Hypoglycemia unawareness identified by continuous glucose monitoring system is frequent in outpatients with type 2 diabetes without receiving intensive therapeutic interventions.

BACKGROUND: Patients with diabetes are prone to asymptomatic hypoglycemia (AH) due to diminished ability to perceive the onset of hypoglycemia. However, the actual prevalence and influencing factors of AH in outpatients with type 2 diabetes (T2DM) have not been well investigated. METHODS: A total of 351 outpatients with T2DM underwent glucose monitoring by continuous glucose monitoring system (CGMS) for consecutive 72 h without changing their lifestyle and treatment regimens. Hypoglycemia is defined as a blood glucose level less than 3.9 mmol/L, which was further divided into Level 1 hypoglycemia (blood glucose 3.0-3.9 mmol/L) and Level 2 hypoglycemia (blood glucose < 3.0 mmol/L). Univariate and multivariate logistic regression analyses were used to determine the possible risk factors of AH. RESULTS: In all 351 subjects studied, 137 outpatients (39.0%) were captured AH events, in which Level 1 AH and Level 2 AH accounted for 61.3% and 38.7%, respectively. 85 (62.0%) of the AH patients experienced nocturnal asymptomatic hypoglycemia (NAH) and 25 (18.2%) exclusively NAH. Multivariate logistic regression analysis demonstrated that patients with younger age, lower hemoglobin A1c (HbA1c), and higher systolic blood pressure (SBP) levels were associated with increased risk of AH. While after further grading of AH, male sex and Dipeptidylpeptidase-4 inhibitors (DPP4i) regime were shown to be associated with lower risk of Level 2 AH. CONCLUSIONS: Hypoglycemia unawareness could be frequently observed at either daytime or nighttime, although NAH was more common, in outpatients with T2DM. Relative relax HbA1c targets should be considered for patients who are prone to AH.

Associations of apnea hypopnea index and educational attainments with microvascular complications in patients with T2DM.

PURPOSE: The relationship between obstructive sleep apnea (OSA) and diabetic microvascular complications (DMC) are controversial. Whether low education is associated with increased risk of DMC independently of poor lifestyles are currently unknown. The aim of this study is to explore the independent associations of different PSG index and educational attainment with risks of DR, DKD, and DPN. METHODS: A cross-sectional study of 330 patients with T2DM who underwent overnight polysomnography (PSG) tests. Multivariable logistic regression analysis was performed to determine the associations of PSG index and educational attainments with DR, DKD, and DPN. RESULTS: The prevalence rates of DMC were 30.6% for DR, 24.9% for DKD, and 64.6% for DPN. All PSG index (AHI, REM-AHI, NREM-AHI, the severity of OSAS, ODI, MAI, and lowest SaO2) were not significantly associated with risks of DR, DKD, or DPN with adjustment for potential confounding factors. Subjects with increasing educational attainments showed significantly decreased prevalence rates of DR (42.6, 27.3, and 21.3%, p = 0.005), DKD (31.7, 25.3, and 14.7%, p = 0.035) and DPN (74.3, 63.6, and 53.3%, p = 0.015), respectively. Logistic regression analyses showed that educational attainment of primary or below showed significantly increased risks of DR (OR (95% CIs): 3.596 (1.453-8.899, p = 0.006)) and DKD (OR (95% CIs): 3.201 (1.244-8.242, p = 0.016)) as compared with that of college or above. There were significant trends of lower educational attainment with increased risks of DR and DKD (p values < 0.05). CONCLUSION: PSG index were not significantly associated with DMC. But lower education was significantly associated with increased risks of DR and DKD, and strategies to prevent DMC for those with low education should be strengthened.

The Ag-promoted α-C-H arylation of alcohols.

We herein report the functionalization of α-C-H in alcohols through cross-dehydrogenative coupling reactions. Selectfluor was used as a mild oxidant. In situ-generated HF participated in the reaction and no external strong acid was necessary. A variety of heteroaryl-substituted alcohols were achieved with good yields and with good functional group tolerance.