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The peptidyl-prolyl cis/trans isomerase NIMA-interaction 1 (Pin1) catalyzes the transition of the proline ring from the cis to trans conformation, resulting in conformational and functional changes in proteins that are regulated by proline-guided serine/threonine phosphorylation. In recent years, Pin1 has emerged as a novel molecular target for the diagnosis and treatment of various malignant tumors. Notably, it has been found that Pin1 is highly expressed in pancreatic cancer. This article focuses on the mechanisms by which Pin1 orchestrates multiple oncogenic functions in the development of pancreatic cancer. By exploring the intricate interactions between Pin1 and the pancreatic tumor microenvironment, we provide an overview of Pin1's role in modifying glycolytic metabolism, redox balance, and the hypoxic microenvironment of pancreatic cancer. Furthermore, we summarize the potential anticancer effects of Pin1 inhibitors, aiming to elucidate Pin1's promise as a potential anticancer agent, particularly in the context of pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prolyl hydroxylase domain 2 (PHD2) is an important enzyme in the human body that perceives changes in oxygen concentration and regulates response in hypoxic environments. Evaluation of PHD2 inhibitory activity of natural products is crucial for drug development of hypoxia related diseases. At present, the detection of low concentration of α-ketoglutaric acid (the substrate of PHD2 enzymatic reaction) requires derivatization reactions or sample pretreatment, which undoubtedly increases the workload of PHD2 inhibitory activity evaluation. In this paper, a direct detection approach of α-ketoglutaric acid was established by using the online stacking strategy of capillary electrophoresis to evaluate the PHD2 inhibitory activity of natural products. Under optimized conditions, detection of a single sample can be achieved within 2 min. By calculation, the intraday precision RSD of the apparent electrophoretic mobility and peak areas of α-ketoglutaric acid are 0.92 % and 0.79 %, respectively, and the interday RSD were 1.27 % and 0.96 % respectively. The recoveries of the present approach were 97.9-105.2 %, and the LOQ and LOD were 2.0 μM and 5.0 μM, respectively. Furthermore, this approach was applied for the evaluation of inhibitory activity of PHD2 for 13 natural products, and PHD2 inhibitory activity of salvianolic acid A was firstly reported. The present work not only realizes evaluation of PHD2 inhibitory activity through direct detection of α-ketoglutaric acid, but also provides technical support for the discovery of potential drug molecules in hypoxia related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Eight previously unreported sesquiterpene coumarins, namely (+)- and (-)-ferulasinkian A (1), (-)-fukanefuromarin M (2), (±)-ferulasinkian C (3), (±)-ferulasinkian D (4), ferulasinkian E (5), ferulasinkian F (7), and ferulasinkian G (8), together with two known compounds, (+)-fukanefuromarin M (2) and 7-hydroxyferprenin (6), have been isolated from the roots of Ferula sinkiangensis (Umbelliferae). The structures of all compounds were elucidated by spectroscopic analysis, along with ECD calculations and optical rotation calculations. Compounds 1-6 are dimers consisting of a chain sesquiterpene and a coumarin with an oxygen-containing six-membered ring connected from coumarin C-3 and C-4. Currently, there are only seven such structures reported in the genus Ferula, and their absolute configurations have not yet been determined. Compounds 7-8 are sesquiterpene coumarin derivatives with a chain sesquiterpene connected with coumarin C-4. In the present study, the chiral separation of compounds (±)-1 and (±)-2 was successfully carried out, and the absolute configurations of compounds (±)-1, (±)-2, 5, 7 and 8 were determined. The isolates were evaluated for their cytotoxic activity against human pancreatic cancer cell lines including CFPAC-1, PANC-1, CAPAN-2 and SW 1990. Compounds (+)-1, (-)-1 and 7 exhibited potent cytotoxicity against pancreatic cancer cells with IC 50 values ranging from 4.57 ± 0.94 to 14.01 ± 1.03 μM. Furthermore, the primary mechanistic study of (-)-1 demonstrated that it could induce apoptosis in CFPAC-1 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To investigate low-frequency fluctuation amplitude changes in resting-state brain fMRI and its correlation with clinical hearing levels in patients with clinical hearing level in patients with unilateral hearing impairment. Methods: Forty-five patients with unilateral hearing impairment[12 males and 33 females, aged 36-67 (46.0±9.7) years], and 31 controls with normal hearing[9 males and 22 females, aged 36-67 (46.0±10.1) years], were retrospectively included. All subjects underwent blood oxygen level-dependent (BOLD) resting-state functional magnetic resonance imaging and high-resolution T1-weighted imaging. The patients were divided into the left-sided hearing impaired group(24 cases), and the right-sided hearing impaired group(21 cases). After data being preprocessed, differences in low frequency amplitude (ALFF) metrics between the evaluated patients and controls were calculated and analyzed, and the statistics were corrected for Gaussian random field (GFR). Results: Overall comparative analysis of patients with hearing impairment showed that one-way ANOVA among the three groups showed abnormal ALFF values only in the right anterior cuneiform lobe (GRF adjusted P =0.002). The ALFF value of the hearing impaired group was higher than that of the control group in one cluster (peak coordinates: X =9, Y =-72, Z =48, T =5.82), involving the left occipital gyrus, right anterior cuneiform lobe, left superior cuneiform lobe, left superior parietal gyrus, and left angular gyrus (GRF adjusted P =0.031). The ALFF value of the hearing impaired group was lower than that of the control group in three clusters (peak coordinates: X =57, Y =-48, Z =-24; T =-4.99; X =45, Y =-66, Z =0, T =-4.06; X =42, Y =-12, Z =36, T =-4.03), involving the right inferior temporal gyrus, the right middle temporal gyrus, and the right precentral gyrus (GRF adjusted P =0.009). Compared with the control group, the ALFF value of the left hearing impairment group was significantly higher than that of the control group in one cluster (peak coordinates: X =-12, Y =-75, Z =45, T =5.78), involving the left anterior cuneiform lobe, right anterior cuneiform lobe, left middle occipital gyrus, left superior parietal gyrus, left superior occipital gyrus, left cuneiform lobe, and right cuneiform lobe ( P =0.023 after GRF correction). Compared with the control group, the right hearing impairment group had a significantly higher ALFF value in one cluster (peak coordinates: X =9, Y =-46, Z =22, T =6.06), involving the left middle occipital gyrus, right anterior cuneiform lobe, left cuneiform lobe, right cuneiform lobe, left superior occipital gyrus, and right superior occipital gyrus (GRF adjusted P =0.022); The brain area with reduced ALFF values is located in the right inferior temporal gyrus (GRF adjusted P =0.029). Spearman's two-tailed correlation analysis between ALFF values and pure tone average in the abnormal brain regions showed that ALFF values in the abnormal brain regions correlated to some extent with the pure tone average (PTA) only in the left-sided hearing impaired group(PTA=2 000 Hz, r =0.318, P =0.033;PTA=4 000 Hz, r =0.386, P =0.009). Conclusion: The abnormal neural activity within the brain are different in patients with left-sided and right-sided hearing impairment, and the severity of hearing impairment is related to the difference in functional integration of brain regions.

Various physiological and pathological changes are related to the occurrence and development of neurodegenerative diseases. Neuroinflammation is a major trigger and exacerbation of neurodegenerative diseases. One of the main symptoms of neuritis is the activation of microglia. Thus, to alleviate the occurrence of neuroinflammatory diseases, an important method is to inhibit the abnormal activation of microglia. This research evaluated the inhibitory effect of trans-ferulic acid (TJZ-1) and methyl ferulate (TJZ-2), isolated from Zanthoxylum armatum , on neuroinflammation, by establishing the human HMC3 microglial cell neuroinflammation model induced by lipopolysaccharide (LPS). The results showed both compounds significantly inhibited the production and expression of nitric oxide (NO), tumor necrosis factor- α (TNF- α ), and interleukin-1 β (IL-1 β ) contents, and increased the level of anti-inflammatory factor β -endorphin ( β -EP). Furthermore, TJZ-1 and TJZ-2 can inhibit LPS-induced activation of nuclear factor kappa B (NF- κ B). It was found that of two ferulic acid derivatives, both had anti-neuroinflammatory effects by inhibiting the NF- κ B signaling pathway and regulating the release of inflammatory mediators, such as NO, TNF- α , IL-1 β , and β -EP. This is the first report that demonstrates that TJZ-1 and TJZ-2 had inhibitory effects on LPS-induced neuroinflammation in human HMC3 microglial cells, which indicates that two ferulic acid derivates from Z. armatum could be used as potential anti-neuroinflammatory agents.

Oxygen is a necessary substance for life activities, but reduced oxygen utilization due to high altitude exposure and respiratory dysfunction diseases could lead to pathological changes in the organisms. Herein gypenosides, the active ingredients in the food and medicine resource plant Gynostemma pentaphyllum (Thunb.) Makino were found to alleviate hypoxia-induced injury in PC12 cells. Moreover, hypoxia induced an increase in Ca 2+ and reactive oxygen species content, and such patterns were both significantly reduced by gypenosides treatment. At the same time, gypenosides significantly blocked the decrease of both NO content and mitochondrial membrane potential caused by hypoxia. Furthermore, gypenosides gavage treatment significantly prolonged the survival time of C57BL/6 mice in confinement up to 24.3% and enhanced the locomotor ability of mice. Therefore, gypenosides have good neuroprotective effects and hypoxia tolerance activity and have the prospect of being developed as a preventive and therapeutic drug for hypoxia-related diseases. PRACTICAL APPLICATIONS: Gypenosides can enhance tolerance of cells and mice to hypoxia and have the potential to be developed into hypoxia-resistant health food and drugs., (© 2022 Wiley Periodicals LLC.)

Natural products (NPs) were a rich source of diverse bioactive molecules. Most anti-tumor agents were built on natural scaffolds. Nardostachys jatamansi DC. was an important plant used to process the traditional Chinese herbal medicines "gansong". Pancreatic cancer was the fourth most common cause of cancer-related death in the world. Hence, there was an urgent need to develop novel agents for the treatment of pancreatic cancer. In this paper, nardoguaianone L (G-6) is isolated from N. jatamansi , which inhibited SW1990 cells colony formation and cell migration, and induced cell apoptosis. Furthermore, we analyzed the differential expression proteins after treatment with G-6 in SW1990 cells by using iTRAQ/TMT-based quantitative proteomics technology, and the results showed that G-6 regulated 143 proteins' differential expression by GO annotation, including biological process, cellular component, and molecular function. Meanwhile, KEGG enrichment found that with Human T-cell leukemia virus, one infection was the most highly enhanced pathway. Furthermore, the MET/PTEN/TGF-β pathway was identified as a significant pathway that had important biological functions, including cell migration and motility by PPI network analysis in SW1990 cells. Taken together, our study found that G-6 is a potential anti-pancreatic cancer agent with regulation of MET/PTEN/TGF-β pathway.

Twenty-two isolates, including two previously undescribed compounds identified as benzoyltembamide (1) and P-benzoyphenethyl anisate (21), were isolated and identified from a methanol extract of the roots of Zanthoxylum bungeanum Maxim. (Rutaceae) using diverse chromatographic materials and pre-HPLC. Their structures were elucidated on the basis of spectroscopic and spectrometric data analysis such as HR-ESI-MS, 1D and 2D NMR, IR and UV, as well as single-crystal X-ray diffraction for crystalline compounds. All the compounds (except for compound 16) were isolated from the roots of Z. bungeanum for the first time. Selected compounds were evaluated for their antioxidant activities. Compound 18 attenuated the H 2 O 2 -induced cytotoxicity and blocked the accumulation of ROS in SH-SY5Y cells, and exhibited potent neuroprotective activity., Competing Interests: Declaration of Competing Interest The authors declared that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2022. Published by Elsevier B.V.)

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide and is known as "the king of cancers". Currently, gemcitabine (GEM) as the clinical drug of choice for chemotherapy of advanced pancreatic cancer has poor drug sensitivity and ineffective chemotherapy. Nardoguaianone L (G-6) is a novel guaiane-type sesquiterpenoid isolated from Nardostachys jatamansi DC., and it exhibits anti-tumor activity. Based on the newly discovered G-6 with anti-pancreatic cancer activity in our laboratory, this paper aimed to evaluate the potential value of the combination of G-6 and GEM in SW1990 cells, including cell viability, cell apoptosis, colony assay and tandem mass tags (TMT) marker-based proteomic technology. These results showed that G-6 combined with GEM significantly inhibited cell viability, and the effect was more obvious than that with single drug. In addition, the use of TMT marker-based proteomic technology demonstrated that the AGE-RAGE signaling pathway was activated after medication-combination. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) assays were used to validate the proteomic results. Finally, apoptosis was detected by flow cytometry. In conclusion, G-6 combined with GEM induced an increase in ROS level and a decrease in MMP in SW1990 cells through the AGE-RAGE signaling pathway, ultimately leading to apoptosis. G-6 improved the effect of GEM chemotherapy and may be used as a potential combination therapy for pancreatic cancer.

Three unreported dammarane-type triterpenoids with rare skeletons (1-3), along with one undescribed gypenoside (4), were isolated from the aerial parts of Gynostemma pentaphyllum using diverse chromatographic materials and pre-HPLC. Their structures were elucidated on the basis of spectroscopic and spectrometric data, while the absolute configurations of 1-3 were assessed via electronic circular dichroism (ECD) analyses. Notably, compounds 1-3 possess a 3,19-hemiketal bridge in the A ring. Saponin 4 possesses an unreported 20,25-oxa structural moiety. Their antiproliferative effects against HepG2, MCF-7, and DU145 cell lines were screened. Compounds 1-3 displayed moderate cytotoxicity with IC 50 values ranging from 13.7 ± 0.2 to 32.0 ± 1.7 μM., Competing Interests: Declaration of Competing Interest The authors declared that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pancreatic cancer has an extremely poor prognosis, and the clinical drugs for the treatment of pancreatic cancer are usually multi-drug combinations. Therefore, it is necessary to search for and find specific new bioactive agents against pancreatic cancer. Carabrone is a carabrane-type sesquiterpenolide extracted from Carpesium cernuum L., and this natural compound has been reported to be a potential anti-tumor agent. However, there are few reports on the function of carabrone related to anti-tumor activity in pancreatic cancer. Herein, cell experiments indicated that carabrone had anti-proliferation inhibition and anti-migration and anti-invasion activity against SW1990 cells. Furthermore, the tandem mass spectrometry and network pharmacology analysis showed that this activity may be related to the ferroptosis and Hippo signaling pathway. Taken together, our results demonstrated that carabrone exhibited prominent anti-pancreatic cancer activity and could be a promising agent against pancreatic cancer.

Five previously unreported terpenoids, together with fifteen known analogs, were isolated from a methanol extract of the roots and rhizomes of Nardostachys jatamansi. Their structures, including absolute configurations, were elucidated by spectroscopic data and electronic circular dichroism (ECD) spectra analyses, as well as single-crystal X-ray diffraction for crystalline compounds. Structurally, (4R,5S,6S,7R)-1(10)-aristolane-8,9-diacid is a novel 8,9-dicarboxylic acid derivative of aristolane-type sesquiterpenoid. (4R,6S,7R,10S)-10-Hydroxyguaia-1(5)-6,7-epoxy-2-one is an undescribed analogue of nardoguaianone K, with a rare 6,7-epoxide group. (4R,5R,6R,8R)-1(10)-Isonardosinone-8-ol-9-one-7,11-lactone is an isonardosinane-type sesquiterpene bearing a γ-lactone ring. Dinardokanshone F is a rare example of a sesquiterpene dimer from N. jatamansi connected by an oxo bridge. The isolates were evaluated for their cytotoxic activity against four human pancreatic cancer cell lines (CFPAC-1, PANC-1, CAPAN-2 and SW1990). Compound epoxynardosinone exhibited significant cytotoxicity against CAPAN-2 cell lines with IC 50 value of 2.60 ± 1.85 μM. 1-Hydroxylaristolone displayed comparable cytotoxicity on CFPAC-1 cell lines (IC 50 1.12 ± 1.19 μM), compared to Taxol (IC 50 0.32 ± 0.13 μM). 1-Hydroxylaristolone, 1(10)-aristolane-9β-ol, 1(10)-aristolen-2-one, alpinenone, valtrate isovaleroyloxyhydrine and nardostachin displayed stronger cytotoxicity against PANC-1 cell lines with IC 50 values ranging from 0.01 ± 0.01 to 6.50 ± 1.10 μM. 1(10)-Aristolane-9β-ol, 10-hydroxyguaia-1(5)-6,7-epoxy-2-one, nardoguaianone K, nardonoxide, epoxynardosinone, 1(10)-isonardosinone-8-ol-9-one-7,11-lactone, valtrate isovaleroyloxyhydrine and nardostachin showed remarkable cytotoxicity against SW1990 cell lines with IC 50 values ranging from 0.07 ± 0.05 to 4.82 ± 6.96 μM. Furthermore, the primary mechanistic study of nardostachin demonstrated that it induced cell apoptosis via the mitochondria-dependent pathway, and induced SW1900 cell arrest at G2/M phase., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To explore the changes of cerebral blood perfusion in patients with unilateral sudden sensorineural hearing loss (SSNHL) by using the three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) technique. Methods: The clinical characteristics and ASL data of the 32 patients with unilateral SSNHL were retrospectively collected from November 2020 to June 2021 in Beijing Fuxing Hospital of Capital Medical University, among them, there were 7 males and 25 females, aged from 17 to 73 (44.9±14.4) years. According to the location of SSNHL, they were divided into the left SSNHL (L-SSNHL) group (18 cases) and the right SSNHL (R-SSNHL) group (14 cases). A total of 34 healthy volunteers, which including 14 males and 20 females, aged from 24 to 68 (46.2±14.4) years were enrolled from the local community. The parameter of cerebral blood flow (CBF) of each brain area was obtained using the CereFlow software. The Brainnetome Atlas software package based on MATLAB was used for visualization. The independent-samples t test was conducted to compare the difference of cerebral blood perfusion between the unilateral SSNHL group and healthy control (HC) group. Pearson correlation analysis was used to evaluate the correlation between changes in cerebral blood perfusion and clinical scale scores. Results: The CBF of left orbital gyrus part 5, left inferior temporal gyrus part 7, right orbital gyrus part 5, right inferior temporal gyrus part 1, right inferior temporal gyrus part 7, and right parahippocampal gyrus part 3 of the L-SSNHL group were higher than that in the HC group[(49.1±8.8) vs (31.6±10.9)ml·100g -1 ·min -1 ;(42.8±14.3) vs (27.1±13.6)ml·100g -1 ·min -1 ;(51.8±9.4) vs (27.2±11.2)ml·100g -1 ·min -1 ;(38.8±5.7) vs (28.0±9.2)ml·100g -1 ·min -1 ;(38.4±13.8) vs (23.6±10.3)ml·100g -1 ·min -1 ;(42.4±9.4) vs (30.1±12.6)ml·100g -1 ·min -1 ; all P <0.05]. The CBF of left superior frontal gyrus part 7 and left middle frontal gyrus part 3 of the L-SSNHL group were lower than that in the HC group[(48.2±7.9) vs (59.3±13.7)ml·100g -1 ·min -1 ;(46.4±10.3) vs (59.3±16.9)ml·100g -1 ·min -1 ;all P <0.05]. The CBF of left orbital gyrus part 5, right orbital gyrus part 5, right inferior temporal gyrus part 1, and right inferior temporal gyrus part 7 of the R-SSNHL group were higher than that in the HC group[(50.6±7.0) vs (31.6±10.9)ml·100g -1 ·min -1 ;(50.9±8.8) vs (27.2±11.2)ml·100 g -1 ·min -1 ;(38.0±7.2) vs (28.0±9.2)ml·100g -1 ·min -1 ;(35.7±8.5) vs (23.6±10.3)ml·100g -1 ·min -1 ;all P <0.05]; the CBF of right insular part 4 was lower than that in the HC group [(44.2±6.1) vs (54.4±11.3) ml·100 g -1 ·min -1 , P =0.018]. In the L-SSNHL group, the CBF of left superior frontal gyrus part 7 and right orbital gyrus part 5 were negatively correlated with the VAS score( r =-0.83, -0.81, all P <0.05), and the CBF of right orbital gyrus part 5 was negatively correlated with the THI score( r =-0.75, P =0.013). There was no statistically significant correlation between the remaining differences in brain regions and clinical scale scores(all P >0.05). Conclusion: Changes in cerebral blood perfusion in multiple brain regions were found in patients with unilateral SSNHL by using the 3D pCASL technique.

Escherichia coli has been known to cause a variety of infectious diseases. The conventional enzyme-linked immunosorbent assay (ELISA) is a well-known method widely used to diagnose a variety of infectious diseases. This method is expensive and requires considerable time and effort to conduct and complete multiple integral steps. We previously proposed the use of paper-based ELISA to rapidly detect the presence of E. coli . This approach has demonstrated utility for point-of-care (POC) urinary tract infection diagnoses. Paper-based ELISA, while advantageous, still requires the execution of several procedural steps. Here, we discuss the design and experimental implementation of a turntable paper-based device to simplify the paper-based ELISA protocols for the detection of E. coli . In this process, antibodies or reagents are preloaded onto zones of a paper-based device and allowed to dry before use. We successfully used this device to detect E. coli with a detection limit of 10 5 colony-forming units (colony-forming unit [CFU])/mL.

To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC 50 values in range of 0.89-11.41 μM, and kinases inhibition against Aurora A and B with the IC 50 values were 9.3 and 2.8 nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor., (Copyright © 2019. Published by Elsevier Ltd.)

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors., (Copyright © 2018. Published by Elsevier Ltd.)

A series of 4β-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 μM. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

We found that the deoxypodophyllotoxin derivative, 2,6-dimethoxy-4-(6-oxo-(5R,5aR,6,8,8aR,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)phenyl ((R)-1-amino-4-(methylthio)-1-oxobutan-2-yl)carbamate (DPMA), exhibited superior cytotoxicity compared with etoposide. In this study, we investigated the mechanism of action of DPMA. DPMA exhibited anti-proliferative activity and induced apoptosis in A549 cells in a dose- and time-dependant manner. DPMA inhibited microtubule formation and induced expression of Bax, cleaved caspase-3, p53 and ROS, and inhibited Bcl-2 expression. DPMA also affected cyclinB1, cdc2 and p-cdc2 expression, inducing cell cycle arrest. DPMA also inhibited tube formation of VEGF-induced human umbilical vein endothelial cells. These studies demonstrate that DPMA inhibits p53/cdc2/Bax signaling, thereby inhibiting cell growth/angiogenesis and inducing apoptosis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of 4β-amino-4'-O-demethyl-4-deoxypodophyllotoxin derivatives were synthesized, and their cytotoxicities against several human cancer cell lines, including HepG2, A549, HeLa and HCT-8 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-N-(4-Nitrophenyl piperazinyl)-4'-O-demethyl-4-deoxypodophyllotoxin (11) was found to be the most potent synthesized compound in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of cdc2, cyclin B1, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Carbamate derivatives of 4β-(1,2,3-triazol-1-yl)podophyllotoxin were synthesized by means of click chemistry, and their cytotoxicities against human cancer cell lines HL-60, A-549, HeLa, and HCT-8 were evaluated. Some compounds were more potent than the anticancer drug etoposide. 4'-O-Demethyl-4β-[(4-hydroxymethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin cyclopentyl carbamate, the most potent compound, induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells. Furthermore, this compound inhibited the formation of microtubules in A-549 cells and caused the inhibition of DNA topoisomerase-II., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A series of carbamate derivatives of 4'-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-4'-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)