Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs.

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Two New Eudesmane-Type Sesquiterpene from Clonostachys sp. Y6-1and Their Cytotoxic Activity.

Two undescribed eudesmane-type sesquiterpenoids together with four known compounds were isolated from Clonostachys sp. Y6-1 associated. Their chemical structures were unambiguously determined by NMR, mass spectrometry, and 13 C-NMR calculation as well as DP4+ probability analyses. The absolute configurations of compounds 1 and 2 were determined by ECD calculation and X-ray single-crystal diffraction methods. Furthermore, all isolates were evaluated for in vitro cytotoxic activities against MCF-7, HCT-116, MDA-MB-231, and SW620 cancer cells. Among them, bioactivity evaluation of compound 5 revealed that weak activity (IC50 =66.55±0.82 µM) against SW620.

Two new compounds from Verbena bonariensis.

Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2-3 and 5-16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line.

Callicarpnoids A-C, structurally intriguing ent-Clerodane diterpenoid dimers with cytotoxicity against MCF-7 and HCT-116 cell lines from Callicarpa arborea Roxb.

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC50 ranging from 5.2 to 7.2 µM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

Ten new prenylated flavonoids from Macaranga denticulata and their antitumor activities.

Ten new prenylated flavonoids, named denticulains A-J (1-10), together with seven known prenylated flavonoids (11-17) were isolated from Macaranga denticulata. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison with literature data. In addition, compounds 1 and 14 inhibited the proliferation of SW620 and HCT-116 cell lines with an IC50 value of 46.08 µM and 56.83 µM, respectively.

The relationship between PRDM16 promoter methylation in abdominal subcutaneous and omental adipose tissue and obesity.

OBJECTIVE: To explore the relationship between PR domain containing 16 (PRDM16) gene promoter methylation in abdominal subcutaneous adipose tissue (SAT) and omental adipose tissue (OAT) and obesity. METHODS: Participants were divided into overweight/obesity (33 cases) and normal-weight groups (28 cases). PRDM16 promoter methylation in abdominal SAT and OAT were detected. Two independent sample t test, paired t test were used to analyze. RESULTS: (1) The methylation levels in overweight/obesity group and normal-weight group were different. There were 3 CpG sites different statistically between two groups. To chr1: 2987447 in SAT and chr1: 2986395 in OAT, the methylation level of normal-weight group was higher. While to chr1: 2987450 in OAT, the methylation level of normal-weight group was lower. (2) The methylation levels in SAT and OAT were different. There were 15 CpG sites different statistically in normal-weight group, and 22 CpG sites in overweight/obesity group. There were 7 CpG sites different statistically in both groups with their methylation levels being higher in OAT than that in SAT. (3) There were 9 haplotypes with statistical significance (8 in SAT, 1 in OAT). CONCLUSION: The methylation degree of PRDM16 gene promoter in abdominal SAT and OAT has the complex relationship with overweight/obesity. The variation of methylation haplotypes combination of multiple sites may play some roles.

Sampling can be faster than optimization.

Optimization algorithms and Monte Carlo sampling algorithms have provided the computational foundations for the rapid growth in applications of statistical machine learning in recent years. There is, however, limited theoretical understanding of the relationships between these 2 kinds of methodology, and limited understanding of relative strengths and weaknesses. Moreover, existing results have been obtained primarily in the setting of convex functions (for optimization) and log-concave functions (for sampling). In this setting, where local properties determine global properties, optimization algorithms are unsurprisingly more efficient computationally than sampling algorithms. We instead examine a class of nonconvex objective functions that arise in mixture modeling and multistable systems. In this nonconvex setting, we find that the computational complexity of sampling algorithms scales linearly with the model dimension while that of optimization algorithms scales exponentially.

Anthropometric indices as surrogates for estimating abdominal visceral and subcutaneous adipose tissue: A meta-analysis with 16,129 participants.

AIM: To seek anthropometric indices that estimate visceral and subcutaneous adipose tissue (VAT and SAT) by meta-analysis and comparing the predictive efficacy based on different characteristics of participants. METHODS: PubMed, PubMed Central, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched for publications containing correlation coefficients of VAT and/or SAT with waist circumference (WC) and/or body mass index (BMI). The overall or subgroup pooled results were analyzed by meta and metafor packages of R with random effects model. MedCalc software was used to compare the correlation coefficients between groups. RESULTS: Twenty-nine publications were included in this meta-analysis. The correlation coefficients of VAT-WC, VAT-BMI, SAT-WC and SAT-BMI for total studies were between 0.640 and 0.785. The correlation of VAT with WC was larger than that with BMI (Z = 11.664, P < 0.001). Meanwhile, the correlation coefficients of VAT-WC were statistically different among different age groups, areas, ethnicities, body shapes, scanning levels, units and instruments of measuring VAT (P < 0.05). The overall correlation of SAT with BMI was larger than that with WC (Z = 3.805, P < 0.001). The subgroups' correlation coefficients of SAT-BMI showed statistical differences between genders, age groups, areas, ethnicities, body shapes, scanning levels, units (cm2 and cm3) and instruments of measuring SAT (P < 0.05). CONCLUSIONS: WC may be a common and simple surrogate for estimating VAT, and BMI for SAT, especially in Europeans, but not in the aged people.

The polymorphism of rs266729 in adiponectin gene and type 2 diabetes mellitus: A Meta-Analysis.

Genome-wide association studies and meta-analyses indicate that the polymorphism of rs266729 in adiponectin gene increases the risk of type 2 diabetes mellitus (T2DM); however, these study methods have not been able to identify the underlying genetic effect on the development of T2DM. A genetic model-free approach was conducted to determine the underlying genetic model of inheritance of T2DM because of rs266729 in adiponectin gene.We searched available studies on the association between the rs266729 in adiponectin gene and T2DM in accordance with the inclusion and exclusion criteria. Based on the information extracted from the studies, generalized odds ratio value (GOR) was used to evaluate whether the rs266729 polymorphism was a risk factor for T2DM. The parameter λ was calculated to estimate the genetic model, which was defined as the quotient of natural logarithm odds ratio of GC to CC divided by the natural logarithm odds ratio of GG to CC. Finally, binary logistic regression analysis was used to calculate the genetic effect of rs266729 on T2DM.Data from 7 studies were included in this meta-analysis. The total number of subjects was 12,323, comprising 5,948 cases and 6,395 controls. Mean (standard deviation) age of cases was 59.50 (11.53), and that of the controls was 53.80 (11.65), whereas the proportion of male was 40.9 and 50.0%, respectively. GOR was 1.13 (1.02, 1.25) and λ was 0.47 (0.29, 0.64). The result of logistic regression indicated that the G allele influenced the development of T2DM in the additive model, whereas the genetic effect was 1.13 (1.06, 1.19). Sources of control populations were the cause of between-study heterogeneity; nonetheless, there was no publication bias among studies.The G allele of rs266729 in adiponectin gene increases the risk of T2DM through an additive genetic model with an effect of 1.13 (1.06, 1.19).