Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents.

Two different synthetic approaches to novel heterocyclic hybrid compounds of 4-azapodophyllotoxin were investigated. The obtained products were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. MTT protocol was then performed to examine the cytotoxic activity of these products against KB, HepG2, A549, MCF7, and Hek-293 cell lines. The cytotoxic assessment indicated that all products displayed moderate to high cytotoxicity against all tested cancer cell lines. The most active compound 13k containing the 2-methoxypyridin-4-yl group exhibited selective cytotoxicity against KB, A549, and HepG2 cell lines with the IC50 values ranging from 0.23 to 0.27 µM, which were between 5- to 10-fold more potent than the positive control ellipticine. Compounds 13a (HetAr = thiophen-3-yl) and 13d (HetAr = 5-bromofuran-2-yl) displayed high cytotoxic selectivity for A549 and HepG2 cancer cell lines when compared to the other cancer cell lines and low toxicity to the normal Hek-293 cell line. Molecular docking study was conducted to evaluate the interaction of new synthesized compounds with the colchicine-binding-site of tubulin. Besides that, physicochemical and pharmacokinetic properties of the most active compounds 13h,k were predicted.

Garcimckeans A-C, three new xanthones from the stems of Garcinia mckeaniana, and their cytotoxic activity.

Three new xanthones, garcimckeans A-C (1-3) were isolated from the methanol extract of the stems of Garcinia mckeaniana (Clusiaceae). Their structures were established by extensive spectroscopic analysis (HR-ESI-MS and 1 D and 2 D NMR) and by comparison of the spectral data with those reported in the literature. Compounds 1-3 displayed weak cytotoxic activity toward KB, Lu, HepG2, and MCF7 cell lines using the MTT assay with IC50 values ranging from 71.03 ± 2.93 to 90.40 ± 7.13 µM compared to that of the positive control compound, ellipticine (IC50: 1.22 ± 0.10 ∼ 2.44 ± 0.2 µM).

Chemical Profile and Biological Activities of Fungal Strains Isolated from Piper nigrum Roots: Experimental and Computational Approaches.

The current report describes the chemical investigation and biological activity of extracts produced by three fungal strains Fusarium oxysporum, Penicillium simplicissimum, and Fusarium proliferatum isolated from the roots of Piper nigrum L. growing in Vietnam. These fungi were namely determined by morphological and DNA analyses. GC/MS identification revealed that the EtOAc extracts of these fungi were associated with the presence of saturated and unsaturated fatty acids. These EtOAc extracts showed cytotoxicity towards cancer cell lines HepG2, inhibited various microbacterial organisms, especially fungus Aspergillus niger and yeast Candida albicans (the MIC values of 50-100 µg/mL). In α-glucosidase inhibitory assay, they induced the IC50 values of 1.00-2.53 µg/mL were better than positive control acarbose (169.80 µg/mL). The EtOAc extract of F. oxysporum also showed strong anti-inflammatory activity against NO production and PGE-2 level. Four major compounds linoleic acid (37.346 %), oleic acid (27.520 %), palmitic acid (25.547 %), and stearic acid (7.030 %) from the EtOAc extract of F. oxysporum were selective in molecular docking study, by which linoleic and oleic acids showed higher binding affinity towards α-glucosidase than palmitic and stearic acids. In subsequent docking assay with inducible nitric oxide synthase (iNOS), palmitic acid, oleic acid and linoleic acid could be moderate inhibitors.

Natural Prenylated Xanthones as Potential Inhibitors of PI3k/Akt/mTOR Pathway in Triple Negative Breast Cancer Cells.

Three prenylated xanthones, garcinone E (1: ), bannaxanthone D (2: ) and bannanxanthone E (3: ) were isolated from the leaves of Garcinia mckeaniana Graib. Their structures were elucidated by spectral methods and compared with literature data. To evaluate their anti-proliferative effects in tumor cells, firstly, cisplatin was used as a positive control and the effects of compound 1:  - 3: were determined by performing MTT assay in MDA-MB-231, CNE-2 and A549 cancer cells. The results showed compound 1:  - 3: exhibited stronger inhibitory effect than cisplatin in MDA-MB-231. Further effects of compound 1:  - 3: in TNBC MDA-MB-231 and MDA-MB-468 cells were examined by performing cell cycle and apoptosis assays. The results indicated that compound 1:  - 3: had ability to arrest cell cycle at G2/M phase and induce apoptosis. Furthermore, compound 2: significantly down-regulated PI3K, Akt and mTOR levels in both total proteins and phosphorylated form, which is its potential anti-cancer mechanism. These findings indicated that those prenylated xanthones might serve as promising leading compounds for the development of anticancer drug for TNBC.

A new cytotoxic compound from the leaves of Styrax annamensis Guillaumin.

New propene derivative 1-(3',4'-methylenedioxyphenyl)-2-(2''-hydroxy-5-(3'''-hydroxypropyl)-3''-methoxyphenyl)prop-2-en-1-one (1), along with three known triterpenoids ursolic acid (2), pomolic acid (3), and maslinic acid (4) were isolated from the leaves of Styrax annamensis species. All structures were assigned by spectroscopic analysis. Compound 1 showed potent cytotoxicity against four cancer cell lines (KB, HepG2, Lu, and MCF7) with the IC50 values of 3.19, 2.87, 2.33, and 2.44 µM, respectively.

A new flavonoid from the leaves of Garcinia mckeaniana Craib and α-glucosidase and acetylcholinesterase inhibitory activities.

From the ethyl acetate extract (EtOAc) of the Vietnamese Garcinia mckeaniana leaves, a new flavone 8-C-glycoside 2'',6''-di-O-acetylvitexin (1), together with six known analogs 2-7 were isolated. Their structures were determined by spectral methods and compared with literature data. In α-glucosidase inhibitory assay, the EtOAc extract and its flavone and biflavone derivatives possessed the significant IC50 range of 9.17-97.53 µM, as compared with that of the positive control acarbose (249 µM). Flavones and biflavones showed are better than flavone glycosides in both α-glucosidase and acetylcholinesterase inhibitory activities[Formula: see text].

Antioxidative and α-glucosidase inhibitory constituents of Polyscias guilfoylei: experimental and computational assessments.

Searching for bioactive agents from medicinal plants, eleven constituents were isolated from Polyscias guilfoylei stem for the first time, including a nucleoside uracil (1), two sterols ß-sitosterol (2) and daucosterol (3), a saponin androseptoside A (4), two lignans (+)-pinoresinol (5) and (+)-syringaresinol (6), four phenolic acids protocatechuic acid (7), methyl protocatechuate (8), caffeic acid (9), and 5-O-caffeoylquinic acid (10), and a flavonoid quercitrin (11). Metabolites 1, 4, and 6-11 have never been observed in genus Polyscias before. Phenolic compounds 7 and 9 possessed the respective IC50 values of 21.33 and 13.88 µg/mL in DPPH (2,2-diphenyl-1-picrylhydrazyl) antioxidative assay, as compared with that of the positive control resveratrol (IC50 = 13.21 µg/mL). From density functional theory (DFT) calculated approach, the DPPH free radical scavenging capacity of two compounds 7 and 9 can be explained by the role of OH groups at carbons C-3 and C-4. Antioxidative actions of these two potential agents are followed HAT (H atom transfer) mechanism by OH bond disruption in gas, but SPLET (sequential proton loss electron transfer) mechanism in solvents water and methanol. Compared to 4-OH group, 3-OH group showed better bond disruption enthalpies and better kinetic energies since it reacted with HOO• and DPPH radicals. Sterols 2-3 and flavonoid 11 induced the IC50 values of < 2.0 µg/mL better than the positive control acarbose (IC50 = 184.0 µg/mL) in α-glucosidase inhibitory assay. Their interactions with human intestinal C- and N-terminal domains of α-glucosidase were explored using molecular docking study. The obtained results proved that compounds 2, 3, and 11 bind relatively stronger with the C-terminal domain than to the N-terminal domain through pivotal residues in the binding site and could be hypothesized as mixed inhibitors.

Mapping low-resource contexts to prepare for lung health interventions in four countries (FRESH AIR): a mixed-method study.

BACKGROUND: Effectiveness of health programmes can be undermined when the implementation misaligns with local beliefs and behaviours. To design context-driven implementation strategies, we explored beliefs and behaviours regarding chronic respiratory disease (CRD) in diverse low-resource settings. METHODS: This observational mixed-method study was conducted in Africa (Uganda), Asia (Kyrgyzstan and Vietnam) and Europe (rural Greece and a Roma camp). We systematically mapped beliefs and behaviours using the SETTING-tool. Multiple qualitative methods among purposively selected community members, health-care professionals, and key informants were triangulated with a quantitative survey among a representative group of community members and health-care professionals. We used thematic analysis and descriptive statistics. FINDINGS: We included qualitative data from 340 informants (77 interviews, 45 focus group discussions, 83 observations of community members' households and health-care professionals' consultations) and quantitative data from 1037 community members and 204 health-care professionals. We identified three key themes across the settings; namely, (1) perceived CRD identity (community members in all settings except the rural Greek strongly attributed long-lasting respiratory symptoms to infection, predominantly tuberculosis); (2) beliefs about causes (682 [65·8%] of 1037 community members strongly agreed that tobacco smoking causes symptoms, this number was 198 [19·1%] for household air pollution; typical perceived causes ranged from witchcraft [Uganda] to a hot-cold disbalance [Vietnam]); and (3) norms and social structures (eg, real men smoke [Kyrgyzstan and Vietnam]). INTERPRETATION: When designing context-driven implementation strategies for CRD-related interventions across these global settings, three consistent themes should be addressed, each with common and context-specific beliefs and behaviours. Context-driven strategies can reduce the risk of implementation failure, thereby optimising resource use to benefit health outcomes. FUNDING: European Commission Horizon 2020. TRANSLATIONS: For the Greek, Russian and Vietnamese translations of the abstract see Supplementary Materials section.

Inferring miRNA-disease associations using collaborative filtering and resource allocation on a tripartite graph.

BACKGROUND: Developing efficient and successful computational methods to infer potential miRNA-disease associations is urgently needed and is attracting many computer scientists in recent years. The reason is that miRNAs are involved in many important biological processes and it is tremendously expensive and time-consuming to do biological experiments to verify miRNA-disease associations. METHODS: In this paper, we proposed a new method to infer miRNA-disease associations using collaborative filtering and resource allocation algorithms on a miRNA-disease-lncRNA tripartite graph. It combined the collaborative filtering algorithm in CFNBC model to solve the problem of imbalanced data and the method for association prediction established multiple types of known associations among multiple objects presented in TPGLDA model. RESULTS: The experimental results showed that our proposed method achieved a reliable performance with Area Under Roc Curve (AUC) and Area Under Precision-Recall Curve (AUPR) values of 0.9788 and 0.9373, respectively, under fivefold-cross-validation experiments. It outperformed than some other previous methods such as DCSMDA and TPGLDA. Furthermore, it demonstrated the ability to derive new associations between miRNAs and diseases among 8, 19 and 14 new associations out of top 40 predicted associations in case studies of Prostatic Neoplasms, Heart Failure, and Glioma diseases, respectively. All of these new predicted associations have been confirmed by recent literatures. Besides, it could discover new associations for new diseases (or miRNAs) without any known associations as demonstrated in the case study of Open-angle glaucoma disease. CONCLUSION: With the reliable performance to infer new associations between miRNAs and diseases as well as to discover new associations for new diseases (or miRNAs) without any known associations, our proposed method can be considered as a powerful tool to infer miRNA-disease associations.

Predicting miRNA-disease associations using improved random walk with restart and integrating multiple similarities.

Predicting beneficial and valuable miRNA-disease associations (MDAs) by doing biological laboratory experiments is costly and time-consuming. Proposing a forceful and meaningful computational method for predicting MDAs is essential and captivated many computer scientists in recent years. In this paper, we proposed a new computational method to predict miRNA-disease associations using improved random walk with restart and integrating multiple similarities (RWRMMDA). We used a WKNKN algorithm as a pre-processing step to solve the problem of sparsity and incompletion of data to reduce the negative impact of a large number of missing associations. Two heterogeneous networks in disease and miRNA spaces were built by integrating multiple similarity networks, respectively, and different walk probabilities could be designated to each linked neighbor node of the disease or miRNA node in line with its degree in respective networks. Finally, an improve extended random walk with restart algorithm based on miRNA similarity-based and disease similarity-based heterogeneous networks was used to calculate miRNA-disease association prediction probabilities. The experiments showed that our proposed method achieved a momentous performance with Global LOOCV AUC (Area Under Roc Curve) and AUPR (Area Under Precision-Recall Curve) values of 0.9882 and 0.9066, respectively. And the best AUC and AUPR values under fivefold cross-validation of 0.9855 and 0.8642 which are proven by statistical tests, respectively. In comparison with other previous related methods, it outperformed than NTSHMDA, PMFMDA, IMCMDA and MCLPMDA methods in both AUC and AUPR values. In case studies of Breast Neoplasms, Carcinoma Hepatocellular and Stomach Neoplasms diseases, it inferred 1, 12 and 7 new associations out of top 40 predicted associated miRNAs for each disease, respectively. All of these new inferred associations have been confirmed in different databases or literatures.

Cytotoxic and α-Glucosidase Inhibitory Xanthones from Garcinia mckeaniana Leaves and Molecular Docking Study.

A new racemic xanthone, garmckeanin A (1), and eight known analogs 2-9 were isolated from the ethyl acetate (AcOEt) extract of the Vietnamese Garcinia mckeaniana leaves. Their structures were determined by MS and NMR spectral analyses and compared with the literature. The AcOEt extract showed good cytotoxicity against cancer cell lines KB, Lu, Hep-G2 and MCF7, with IC50 values of 5.40-8.76 µg/mL, and it also possessed α-glucosidase inhibitory activity, with an IC50 value of 9.17 µg/mL. Garmckeanin A (1) exhibited inhibition of all cancer cell lines, with an IC50 value of 7.3-0.9 µM. Allanxanthone C (5) successfully controlled KB growth, with an IC50 value of 0.54 µM, higher than that of the positive control, ellipticine (IC50 1.22 µM). Norathyriol (8) was a promising α-glucosidase inhibitor, with an IC50 value of 0.07 µM, much higher than that of the positive control, acarbose (IC50 161.0 µM). The interactions of the potential α-glucosidase inhibitors with the C- and N-terminal domains of human intestinal α-glucosidase were also investigated by molecular docking study. The results indicated that bannaxanthone D (2), garcinone E (4), bannaxanthone E (6), and norathyriol (8) exhibit higher binding affinity to the C-terminal than to the N-terminal domain through essential residues in the active sites. In particular, compound 8 could be assumed to be the most potent mixed inhibitor.

Medicinal Plant Centipeda Minima: A Resource of Bioactive Compounds.

BACKGROUND: Centipeda minima (the family Asteraceae) is an annual herbaceous plant native to the tropical regions, especially in eastern tropical Asia. C. minima is well-known in the list of medicinal plants with capacities in treatment of whooping cough, nasal allergy, malaria, and asthma. More than sixty reports on phytochemical and pharmacological aspects of this plant are now available, but a supportive review is insufficient. OBJECTIVE: The current review aims to make a compilation of almost all of the isolated compounds from the title plant, together with their pharmacological activities. METHODOLOGY: Centipeda minima is a meaningful keyword to search for previous references, while the reliable databases, such as Sci-Finder, Google Scholar, Pub Med, Science Direct, the Web of Science, Scopus, Bentham science, Taylor Francis, Springer, IOP Science were utilized at most. CONCLUSION: More than one hundred secondary metabolites, classifying as terpenoids, flavonoids, mono-phenols, fatty acids, amides, and other types, were isolated from this plant. Among them, sesquiterpene lactones are dominant in either C. minima species or numerous plants of genus Centipeda. These phytochemical groups also possessed various biological results like anti-cancer, anti-bacteria, anti-allergy, anti-virus, anti-inflammation, and hepatoprotective activities. With many kinds of bioactive results such as anti-cancer and anti-inflammation, the use of C. minima plant extracts and isolated compounds for drug development seems to be a futuristic strategy.

Design, synthesis and evaluation of novel hybrids between 4-anilinoquinazolines and substituted triazoles as potent cytotoxic agents.

In this research several series of novel dioxygenated ring fused 4-anilinoquinazolines (10a-d) and 4-anilinoquinazoline-substituted triazole hybrid compounds (11-14) have been designed and synthesized. Their biological significance was highlighted by evaluating in vitro for anticancer activities, wherein several compounds displayed excellent activity specifically against three human cancer cell lines (KB, epidermoid carcinoma; HepG2, hepatoma carcinoma; SK-Lu-1, non-small lung cancer). Especially, compound 13a exhibited up to 100-fold higher cytotoxicity in comparison with erlotinib. Docking the most cytotoxic compounds (11d, 13a, 13b, and 14c) into the ATP binding site of different EGFR tyrosine kinase domains was perfomed to predict the analogous binding mode of these compounds to the EGFR targets.

Dosing rationale for liraglutide in type 2 diabetes mellitus: a pharmacometric assessment.

The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose-finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure-response relationships for effects on fasting plasma glucose, hemoglobin A(1c), and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure-response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.

GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide.

BACKGROUND: Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. AIM: The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. METHODS: Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy. RESULTS: Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups. CONCLUSIONS: These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies.