Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma.

This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 âˆ¼ 2 µM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure-activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.

Arenobufagin, isolated from Bufo viridis toad venom, inhibits A549 cells proliferation by inducing apoptosis and G2/M cell cycle arrest.

Lung cancer is a significant contributor to cancer morbidity and mortality globally. Arenobufagin, a compound derived from Bufo viridis toad venom, has demonstrated the ability to inhibit cell growth in various cancer cell lines. However, our understanding of the role and mechanism of arenobufagin in lung cancer remains incomplete, necessitating further researches to fully elucidate its action mechanism. In this study, we further explored the impact of arenobufagin on A549 cells. The results revealed that it exerted a potent cytotoxic effect on A549 cells by inhibiting cell colony formation, promoting cell apoptosis, increasing reactive oxygen species (ROS) levels, and arresting A549 cells in G2/M phase. Collectively, our findings suggested that arenobufagin may have potential as a future therapeutic for lung cancer treatment.

Discovery of novel (E)-1-methyl-9-(3-methylbenzylidene)-6,7,8,9-tetrahydropyrazolo[3,4-d]pyrido[1,2-a]pyrimidin-4(1H)-one as DDR2 kinase inhibitor: Synthesis, molecular docking, and anticancer properties.

We report the synthesis, molecular docking and anticancer properties of the novel compound (E)-1-methyl-9-(3-methylbenzylidene)-6,7,8,9-tetrahydropyrazolo[3,4-d]pyrido[1,2-a]pyrimidin-4(1H)-one (PP562). PP562 was screened against sixteen human cancer cell lines and exhibited excellent antiproliferative activity with IC50 values ranging from 0.016 to 5.667 µM. Experiments were carried out using the target PP562 at a single dose of 1.0 µM against a kinase panel comprising 100 different enzymes. A plausible binding mechanism for PP562 inhibition of DDR2 was determined using molecular dynamic analysis. The effect of PP562 on cell proliferation was also examined in cancer cell models with both high and low expression of the DDR2 gene; PP562 inhibition of high-expressing cells was more prominent than that for low expressing cells. PP562 also exhibits excellent anticancer potency toward the HGC-27 gastric cancer cell line. In addition, PP562 inhibits colony formation, cell migration, and adhesion, induces cell cycle arrest at the G2/M phase, and affects ROS generation and cell apoptosis. After DDR2 gene knockdown, the antitumor effects of PP562 on tumor cells were significantly impaired. These results suggested that PP562 might exert its inhibitory effect on HCG-27 proliferation through the DDR2 target.

Germacrane-Type Sesquiterpene Lactones from Achillea millefolium L. and Their Anti-Inflammatory Activity.

Six undescribed germacrane-type sesquiterpene lactones, millefoliumons A-F, and two known analogs were isolated from the ethyl acetate fraction of the whole plant of Achillea millefolium L. growing in Xinjiang, China. The structures of these compounds were fully elucidated by their 1D and 2D nuclear magnetic resonance (NMR), and high resolution mass (HR-ESI-MS) spectral data, and comparison with literatures. The absolute configurations of millefoliumons A-F were confirmed by experimental and calculated electronic circular dichroism data (ECD), and 13 C-NMR calculations and DP4+ probability analysis. All compounds displayed the approximate tendency to inhibit the nitric oxide (NO) release in lipopolysaccharide (LPS)-induced BV2 cells.

Furo[2,3-d]pyrimidines as Mackinazolinone/Isaindigotone Analogs: Synthesis, Modification, Antitumor Activity, and Molecular Docking Study.

The chemical transformation of the tricyclic furo[2,3-d]pyrimidines was performed under isosteric and scaffold-hopping strategies focusing on the synthesis of its arylidene and imine-containing derivatives. Naturally-occurring alkaloids mackinazolinone and isaindigotone were as templates of target heterocycles. Synthesized compounds evaluated for their antitumor activity on human cancer cervical HeLa, breast MCF-7, and colon HT-29 cell lines. Four compounds: 8c, 8e, 10b, and 10c demonstrated potency against HeLa and HT-29 cell lines, and IC50 values were between 7.37-13.72 µM, respectively. The molecular docking results showed that compounds 8c and 10b had good binding and high matching with the target EGFR protein.

Two New C19 -Diterpenoid Alkaloids from Delphinium shawurense.

Shawurenine C (1a) and D (1b), a new pair of regioisomeric C19 -diterpenoid alkaloids, and five known C19 -diterpenoid alkaloids (2-6) were isolated from the aerial part of Delphinium shawurense W. T. Wang. The chemical structures of new compounds were established based on spectroscopic analyses: HR-ESI-MS, and 1D, 2D NMR spectroscopic data. The anti-inflammatory and cytotoxic activities of these diterpenoid alkaloids were also evaluated.

Root-Extracted lignanamides from Limonium gmelinii (Willd.) Kuntze with a potential PTP1B inhibitory activity by regulating PI3K/AKT signaling pathway.

The phytochemical study of Limonium gmelinii roots resulted in the isolation of five lignanamides (1-5). Among them, limoniumins J, K, and M (1, 2, and 4) are undescribed compounds, limoniumin L (3) is a new naturally occurring lignanamide, and limoniumin B (5) is a known compound which showed PTP1B inhibition activity with an IC50 value of 5.05 ± 2.44 µM in our previous work. Spectroscopic data analysis, including 1D and 2D NMR and HRESIMS experiments, established the chemical structures of limoniumins J - M (1-4). Compounds 1-4 showed PTP1B inhibition activity, among which compound 3 showed the most potent PTP1B inhibition with an IC50 value of 2.07 ± 0.05 µM. Compounds 3 and 5 could significantly increase cellular glucose consumption and glucose uptake in L6 muscle cells and could synergize with insulin to promote glucose consumption and glucose uptake in a concentration-dependent manner. The treatment of compound 3 also promoted glycogen synthesis in skeletal muscle cells. Western blot analysis demonstrated that the good hypoglycemic effect of compounds 3 and 5 was achieved by activating PI3K/AKT signaling pathway to promote glucose consumption, glucose uptake, and glycogen synthesis. Furthermore, studies on molecular docking revealed the potent interactions between these bioactive substances and the PTP1B protein.

Anti-Diabetic Effects and Molecular Mechanisms of Amide Alkaloids from Piper longum Based on Network Pharmacology Integrated with Cellular Assays.

Piper longum is a well-known spice and traditional medicine. It was revealed to possess anti-diabetic activity, but few information about its active component and underlying mechanism could be available. In this study, retrofractamides A (1) and C (2) isolated from P. longum showed potent inhibitory activity against PTP1B. Therefore, the potential mechanism was predicted by network pharmacology and molecular docking. PI3K/AKT was obtained as the most remarkable pathway against type 2 diabetes mellitus (T2DM), and AKT1 and GSK3ß were yielded as the top two core targets of retrofractamides A (1) and C (2). Molecular docking of compounds with AKT1 and GSK3ß showed strong binding affinity between them. Additionally, cellular experiments with a L6 cell model was conducted to further verify the above predictions. Results indicated that retrofractamides A (1) and C (2) exerted anti-diabetic effect via activating PI3K/AKT pathway, and they promoted glucose consumption, glucose uptake, glycogen synthesis and glycolysis.

Preparation of arctiin moleculary imprinted polymers with 4-vinylpyridine and Allyl-ß-cyclodextrin as binary monomers under molecular crowding conditions.

This paper reported a feasible method to prepare molecularly imprinted polymer (MIPs) using 4-vinylpyridine (4-VP) and Allyl-ß-cyclodextrin (ß-CD) as binary functional monomer in the presence of polystyrene (PS). This is the first time that a surrounding of macromolecular crowding was established to improve the imprinting effect of cyclodextrins as monomer in organic solvents. The morphological and characteristics of the polymers with macromolecular crowding reagents were investigated by scanning electron microscope (SEM), fourier-transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA) and nitrogen adsorption experiments. The MIPs were synthesized with 4-VP and ß-CD as binary functional monomers, a series of experiments were conducted to compare with the control groups. Furthermore, the selectivity of MIP for analogues experiment showed that the ß-CD/4-VP MIP has higher specific recognition for arctiin than ß-CD/4-VP NIP. A purification method by ß-CD/4-VP MIPs coupled with macromolecular crowding reagents was developed for extraction arctiin from Arctium lappa L. In the MIP-SPE process, the optimal washing and eluting reagents are methanol/water (5:5) and methanol/acid (9:1), respectively. When using the ß-CD/4-VP MIPs as SPE absorbent, the mean recoveries for arctiin were 87% with purity of 95%. All the results indicate that this synthetic method using 4-VP and ß-CD as binary functional monomers in the presence of PS is a promising method for the preparation of selective adsorbents for arctiin analysis in Arctium lappa L.

Chemical profiling of spermidines in goji berry by strong cation exchange solid-phase extraction (SCX-SPE) combined with ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS/MS).

Lycium barbarum fruit (Goji berry) have been used as a traditional Chinese medicine (TCM) with its outstanding biological and pharmacological activities. Spermidine alkaloids are a major class of bioactive constituents in goji berry, nevertheless, detailed information related to its identification remains scarce. In this study, chemical profiling of spermidines in goji berry was carried out by ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Four structure types of standards were used to study the comprehensive fragmentation rules of spermidines. Different types of spermidines were identified by distinctive MS/MS fragment ions. Noticeably, it was first proposed that the co-existence of fragment ions at m/z 220 and 222 was the key characteristic for distinguishing spermidine isomers. According to the structural feature of spermidines, a quick, convenient, highly selective strong cation exchange solid-phase extraction (SCX-SPE) combined with RP-LC procedure was developed for selective enrichment and the MS detection compatibility. A total of 41 out of 58 spermidines were tentatively characterized using the established method, of which 26 were reported for the first time from goji berry. This study provides guidelines and references for the identification of spermidines in natural products.

Metabolic profiling analysis of corilagin in vivo and in vitro using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry.

Corilagin is an Ellagitannin with favorable pharmacological activities. But there was no report regarding the metabolism of corilagin in vitro or in vivo. In this study, the metabolic profile of corilagin in rats as well as in rat intestinal bacteria and liver microsomes incubation system in vitro were investigated comprehensively for the first time. Consequently, with the aid of sensitive HPLC-Q-TOF-MS/MS, corilagin and its twenty-four metabolites (fourteen phase II conjugate metabolites of corilagin, three hydrolyzed metabolites EA, GA, M3 and their seven derived metabolites) were absolutely or tentatively identified in rat biological samples (urine, feces, plasma and tissues) after oral administration of corilagin. In vitro, the three hydrolyzed metabolites were identified in rat intestinal microflora and liver microsomes. These results demonstrated that corilagin itself not only could underwent extensive phase II metabolism in rats, but also could underwent hydrolysis reaction in rats as well as in rat intestinal bacteria and liver microsomes in vitro. This study is first report to identify phase II conjugate metabolites (except mono-methylate conjugated metabolites) of pure Ellagitannin and distribution of these metabolites in vivo. In addition, clear, detailed metabolic pathways of corilagin were shown to involve hydrolysis, methylation, glycosylation, reduction, glucuronidation and sulfation.

Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics.

In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for α1A, 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.

Preparation of phenylboronate affinity rigid monolith with macromolecular porogen.

Boronate-affinity monolithic column was first prepared via polystyrene (PS) as porogen in this work. The monolithic polymer was synthetized using 4-vinylphenylboronic acid (4-VPBA) as functional monomer, ethylene glycol dimethacrylate (EDMA) as crosslinker monomer, and a mixture of PS solution in tetrahydrofuran, the linear macromolecular porogen, and toluene as porogen. Isoquercitrin (ISO) and hyperoside (HYP), isomer diol flavonoid glycosides, can be baseline separated on the poly(VPBA-co-EDMA) monolith. The effect of polymerization variables on the selectivity factor, e.g., the ratio of monomer to crosslinker (M/C), the amount of PS and the molecular weight of macromolecular porogen was investigated. The surface properties of the monolithic polymer were characterized by scanning electron microscopy and nitrogen adsorption. The best polymerization condition was the M/C ratio of 7:3, and the PS concentration of 40 mg/ml. The poly(VPBA-co-EDMA) polymer was also applied to extract cis-diol flavonoid glycosides from the crude extraction of cotton flower. After treated by poly(VPBA-co-EDMA) for solid phase extraction, high purity ISO and HYP (>99.96%) can be obtained with recovery of 83.7% and 78.6%, respectively.

The estrogenic activity of isoflavones extracted from chickpea Cicer arietinum L sprouts in vitro.

Isoflavones have drawn attention due to their potential therapeutic use. Isoflavones are the important chemical components of the seeds and sprouts of chickpea and higher isoflavones in sprouts than in seeds. However, there have been no previous reports of the estrogenic activity of isoflavones extracted from chickpea Cicer arietinum L sprouts (ICS) in vitro. In this study, which incorporated several in vitro bioassays methods, we systematically evaluated the estrogenic properties of ICS. MTT assay showed that ICS at the low concentration ranges (10(-3)-1 mg/L) promoted MCF-7 cell growth, while at high concentrations, (>1 mg/L) inhibited cell proliferation, indicating ICS worked at a diphasic mechanism. Flow cytometric analysis further calculated the proliferation rate of ICS at low concentration (1 mg/L). ERα/Luc trans-activation assay and then semi-quantitative RT-PCR analysis indicated that ICS at low concentrations induced ERα-mediated luciferase activity in MCF-7 cells and promoted the ER downstream target gene pS2 and PR trans-activation. These effects were inhibited by ICI 182,780, a special antagonist of ER, indicating that an ER-mediating pathway was involved. Alkaline phosphatase (AP) expression in Ishikawa cells showed that ICS at low concentrations stimulated AP expression. Our current study is the first to demonstrate that ICS has significant estrogenic activity in vitro. ICS may be useful as a supplement to hormone replacement therapy and in dietary supplements.

New phthalide glycosides from Helichrysum arenarium (L.) Moench.

Two new prenylated phthalide glycosides 1 and 2 were isolated from the whole plant of Helichrysum arenarium, and their structures were elucidated on the basis of spectral data.