Copper-Catalyzed Cascade Annulation of Malonate-Tethered O-Acyl Oximes with Cyclic 1,3-Dicarbonyl Compounds for the Synthesis of Spiro-Pentacyclic Derivatives.

A copper-catalyzed cascade annulation of malonate-tethered O-acyl oximes with cyclic 1,3-dicarbonyl compounds has been developed for the rapid synthesis of spiro-pentacyclic derivatives. This reaction allows the one-step formation of five C-C/N/O bonds and an angular tricyclic core under very mild conditions and shows excellent regioselectivity and stereoselectivity.

Effectiveness of Lifestyle and Drug Intervention on Hypertensive Patients: a Randomized Community Intervention Trial in Rural China.

BACKGROUND: Strict medication guidance and lifestyle interventions to manage blood pressure (BP) in hypertensive patients are typically difficult to follow. OBJECTIVE: To evaluate the 1-year effectiveness of lifestyle and drug intervention in the management of rural hypertensive patients. DESIGN: Randomized community intervention trial. PARTICIPANTS: The control group comprised 967 patients who received standard antihypertensive drug intervention therapy from two communities, whereas the intervention group comprised 1945 patients who received antihypertensive drug and lifestyle intervention therapies from four communities in rural China. MAIN MEASURES: Data on lifestyle behaviors and BP measurements at baseline and 1-year follow-up were collected. A difference-in-difference logistic regression model was used to assess the effect of the intervention. KEY RESULTS: BP control after the 1-year intervention was better than that at baseline in both groups. The within-group change in BP control of 59.3% in the intervention group was much higher than the 25.2% change in the control group (P < 0.001). Along with the duration of the follow-up period, systolic and diastolic BP decreased rapidly in the early stages and then gradually after 6 months in the intervention group (P < 0.001). In the intervention group, drug therapy adherence was increased by 39.5% (from 48.1% at 1 month to 87.6% at 1 year) (P < 0.001), more in women (45.6%) than in men (31.2%; P < 0.001). The net effect of the lifestyle intervention improved the rate of BP control by 56.1% (70.8% for men and 44.7% for women). For all physiological and biochemical factors, such as body mass index, waist circumference, lipid metabolism, and glucose control, improvements were more significant in the behavioral intervention group than those in the control group (all P < 0.001). CONCLUSION: The addition of lifestyle intervention by physicians or nurses helps control BP effectively and lowers BP better than usual care with antihypertensive drug therapy alone.

pKWmEB: integration of Kruskal-Wallis test with empirical Bayes under polygenic background control for multi-locus genome-wide association study.

Although nonparametric methods in genome-wide association studies (GWAS) are robust in quantitative trait nucleotide (QTN) detection, the absence of polygenic background control in single-marker association in genome-wide scans results in a high false positive rate. To overcome this issue, we proposed an integrated nonparametric method for multi-locus GWAS. First, a new model transformation was used to whiten the covariance matrix of polygenic matrix K and environmental noise. Using the transferred model, Kruskal-Wallis test along with least angle regression was then used to select all the markers that were potentially associated with the trait. Finally, all the selected markers were placed into multi-locus model, these effects were estimated by empirical Bayes, and all the nonzero effects were further identified by a likelihood ratio test for true QTN detection. This method, named pKWmEB, was validated by a series of Monte Carlo simulation studies. As a result, pKWmEB effectively controlled false positive rate, although a less stringent significance criterion was adopted. More importantly, pKWmEB retained the high power of Kruskal-Wallis test, and provided QTN effect estimates. To further validate pKWmEB, we re-analyzed four flowering time related traits in Arabidopsis thaliana, and detected some previously reported genes that were not identified by the other methods.

Relationship of "weekend warrior" and regular physical activity patterns with metabolic syndrome and its associated diseases among Chinese rural adults.

Little is known about the "weekend warrior" pattern of physical activity (PA) where people perform all their PA in 1 or 2 sessions per week. We investigated the relationship of weekend warrior and other PA patterns with metabolic syndrome (MS) and its associated diseases. Data on sociodemographic and lifestyle characteristics were collected from the Nantong Metabolic Syndrome Study that included 13,505 women and 6,997 men between 2007 and 2008. Compared with inactive participants, weekend warriors were at lower risk of MS, diabetes, and hypertension; respective odds ratios (95% confidence intervals) for men and women were 0.58 (0.43-0.79) and 0.67 (0.52-0.86), 0.52 (0.34-0.79) and 0.52 (0.33-0.83), and 0.79 (0.63-0.99) and 0.71 (0.57-0.89). Similar results were observed with regular activity, at a frequency of >3 sessions per week. Both weekend warrior and regular PA patterns showed a 10-60% decrease in abnormal triglycerides, glucose, and blood pressure in both sexes; abnormal waist circumference in men only; and abnormal high-density lipoprotein in women only. Our observed cross-sectional relationships reflect that >150 min/week of moderate PA or 75 min/week vigorous-intensity PA is needed to prevent MS and its component diseases, even if in a short-bout, intermittent PA pattern. ABBREVIATIONS: MS: Metabolic syndrome; WC: Waist circumference; TG: Triglycerides; HDL-c: High-density lipoprotein cholesterol; BP: Blood pressure; SBP: Systolic blood pressure, DBP: Diastolic blood pressure; PA: Physical activity; JIS: Joint Interim Statement; CVD: Cardiovascular disease; ATP III: US Third Report of the National Cholesterol Education Program, the Adult Treatment Panel; IDF: International Diabetes Federation; IPAQ: International Physical Activity Questionnaire; BMI: Body mass index; CDC: the Nantong Centers for Disease Control; OR: Odds ratio; CI: Confidence interval; SD: Standard deviation; IQR: Interquartile range.

An Effective Pd-Catalyzed Regioselective Hydroformylation of Olefins with Formic Acid.

An effective palladium-catalyzed regioselective hydroformylation of olefins with formic acid is described. The ligand plays a crucial role in directing the reaction pathway. Linear aldehydes can be obtained in up to 93% yield with >20:1 regioselectivity using 1,3-bis(diphenylphosphino)propane (dppp) as the ligand. The reaction process is operationally simple and requires no syngas.

Pd-Catalyzed regioselective hydroesterification of 2-allylphenols to seven-membered lactones without external CO gas.

Effective Pd-catalyzed regioselective hydroesterification of 2-allylphenols with phenyl formate is described. A variety of seven-membered lactones can be obtained in good yields under mild conditions without the use of toxic CO gas.

An atom-economic approach to carboxylic acids via Pd-catalyzed direct addition of formic acid to olefins with acetic anhydride as a co-catalyst.

An effective Pd-catalyzed hydrocarboxylation of olefins using formic acid with acetic anhydride as a co-catalyst is described. A variety of carboxylic acids are obtained in good yields with high regioselectivities under mild reaction conditions without the use of toxic CO gas.

A facile approach to ß-amino acid derivatives via palladium-catalyzed hydrocarboxylation of enimides with formic acid.

An effective Pd(0)-catalyzed hydrocarboxylation of enimides with formic acid in the presence of a catalytic amount of HCOOPh is described. A variety of ß-amino acid derivatives are obtained in good yields with high regioselectivities without using external toxic CO gas.

A palladium-catalyzed enantioselective hydroesterification of alkenylphenols with phenyl formate. A facile approach to optically active dihydrocoumarins.

An effective palladium-catalyzed enantioselective hydroesterification of alkenylphenols with phenyl formate as a CO source is described. A variety of optically active dihydrocoumarins can be obtained in generally high yields with up to 91% ee.

Pd-Catalyzed Regioselective Hydrocarboxylation of Alkyl Terminal Olefins with Oxalic Acid.

A Pd-catalyzed regioselective hydrocarboxylation of alkyl terminal olefins with oxalic acid is described. A wide variety of linear carboxylic acids can be readily obtained in good yields and high l/b (linear/branched) ratios with Pd2(dba)3 and (p-ClPh)3P under mild conditions. The reaction process is operationally simple and requires no handling of toxic CO. In addition, branched carboxylic acids can also be formed in good regioselectivities with PdCl2 and (2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)diphenylphosphine (L1).

Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

CDK9 targeting PROTAC L055 inhibits ERα-positive breast cancer.

Breast cancer is one of the most prevalent malignancies affecting women worldwide, underscoring the urgent need for more effective and specific treatments. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy to develop new lead compounds by selectively targeting oncoproteins for degradation. In this study, we designed, synthesized and evaluated a CRBN-based PROTAC, L055, which targets CDK9. Our findings demonstrate that L055 effectively inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells in vitro. L055 specifically binds to CDK9, facilitating its degradation via the CRBN-dependent proteasomal pathway. Additionally, L055 suppressed the growth of organoids and tumors derived from T47D and MCF7 cells in nude mice. Thus, L055 represents a potential novel therapeutic agent for ERα-positive breast cancer and potentially other malignancies.

Hypervalent iodine reagent mediated reaction of [60]fullerene with amines.

The hypervalent iodine reagent mediated reaction of C60 with various readily available amines for the easy preparation of iminofullerenes has been developed. The reaction between C60 and sulfonamides can be effectively controlled to selectively synthesize azafulleroids or aziridinofullerenes under PhI(OAc)2/I2 or PhIO/I2/CuCl/lutidine conditions, respectively. For phosphamide and urea, only one isomer is obtained. However, carbamate gives three kinds of products. Interestingly, the reaction of C60 with alkylamines allows the effective synthesis of aziridinofullerenes and regioselective cis-1-bisaziridinofullerenes.

DMAP-catalyzed [3 + 2] and [4 + 2] cycloaddition reactions between [60]fullerene and unmodified Morita-Baylis-Hillman adducts in the presence of Ac2O.

One-step DMAP-catalyzed [3 + 2] and [4 + 2] cycloaddition reactions between C(60) and unmodified Morita-Baylis-Hillman adducts in the presence of Ac(2)O have been developed for the easy preparation of cyclopentene- and cyclohexene-fused [60]fullerene derivatives. When the MBH adducts bear an alkyl group, two different reaction pathways could be controlled selectively depending on the conditions.

Highly stereoselective, one-pot synthesis of azetidines and 2,4-dioxo-1,3-diazabicyclo[3.2.0] compounds mediated by I2.

We report here a convenient method to construct polysubstituted azetidines and 2,4-dioxo-1,3-diazabicyclo[3.2.0] compounds with high stereoselectivities in a one-pot reaction mediated by I2. The tetramethylguanidine (TMG)/I2-mediated formal [2 + 2] cycloaddition reaction of α-amidomalonate 1 with enones 2 affords functionalized azetidine derivatives 4 in moderate to good yields with high diastereoselectivity. When the α-ureidomalonate 5 is used instead of 1, 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptanes 8 and 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptenes 9 can be prepared selectively through the control of solvent and temperature. 2,4-Dioxo-1,3-diazabicyclo[3.2.0]heptanes 8 can further undergo ring-opening reactions with different nucleophilic reagents to afford the corresponding polyfunctionalized azetidine derivatives 13-16 with high steroselectivities.

Pd-Catalyzed Regioselective Hydroformylation of Olefins with HCO2H and Its Derivatives.

An effective Pd-catalyzed regioselective hydroformylation process with N-formylsaccharin or 2,4,6-trichlorophenyl formate along with formic acid is described. Linear aldehydes can be obtained in up to 83% yield and >20:1 l/b ratio. The reaction is operationally simple without the need for external CO and H2.

Pd-Catalyzed Regiodivergent Hydrocarboxylation of Olefins with Oxalic Acid: A Remarkable Effect of the Counteranion on Regioselectivity.

A regioselective Pd-catalyzed hydrocarboxylation of vinyl arenes with oxalic acid is described. A wide variety of either linear or branched carboxylic acids can be readily obtained with high regioselectivities under mild reaction conditions. The reaction process is operationally simple and requires no handling of toxic CO. Besides the ligand, the counteranion of the Pd catalyst system plays an important role in the regioselectivity.

Integrin ß4 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/RAC1.

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer (TNBC) treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote TNBC cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin ß4. Integrin ß4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in TNBC. These results indicate that the Integrin ß4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in TNBC.

Pd-Catalyzed Regioselective Branched Hydrocarboxylation of Terminal Olefins with Formic Acid.

A regioselective Pd-catalyzed hydrocarboxylation of terminal olefins with HCOOH is described. A wide variety of branched carboxylic acids can readily be obtained with high regioselectivities under mild reaction conditions. The reaction is operationally simple and requires no handling of toxic CO. The ligand and LiCl are important factors for reaction reactivity and selectivity.

YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer.

Y-box binding protein 1 (YB-1) is a well-known oncogene highly expressed in various cancers, including basal-like breast cancer (BLBC). Beyond its role as a transcription factor, YB-1 is newly defined as an epigenetic regulator involving RNA 5-methylcytosine. However, its specific targets and pro-cancer functions are poorly defined. Here, based on clinical database, we demonstrate a positive correlation between Kruppel-like factor 5 (KLF5) and YB-1 expression in breast cancer patients, but a negative correlation with that of Dachshund homolog 1 (DACH1). Mechanistically, YB-1 enhances KLF5 expression not only through transcriptional activation that can be inhibited by DACH1, but also by stabilizing KLF5 mRNA in a RNA 5-methylcytosine modification-dependent manner. Additionally, ribosomal S6 kinase 2 (RSK2) mediated YB-1 phosphorylation at Ser102 promotes YB-1/KLF5 transcriptional complex formation, which co-regulates the expression of BLBC specific genes, Keratin 16 (KRT16) and lymphocyte antigen 6 family member D (Ly6D), to promote cancer cell proliferation. The RSK inhibitor, LJH685, suppressed BLBC cell tumourigenesis in vivo by disturbing YB-1-KLF5 axis. Our data suggest that YB-1 positively regulates KLF5 at multiple levels to promote BLBC progression. The novel RSK2-YB-1-KLF5-KRT16/Ly6D axis provides candidate diagnostic markers and therapeutic targets for BLBC.