BIOORGANIC CHEMISTRY
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2024
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IF 4.5
Linlin Han,Hongyan Tan,Jungjoon Lee,Peng Wang,Yuqing Zhao
Based on the significant biological activities and the remarkable physical and chemical properties of 1 H -1,2,3-triazole pharmacophore, we herein adopted the strategy of click chemistry to combine the triazole fragment and the unique scaffold of 25-OCH 3 -PPD ( AD-1 ) to design a series of potent compounds inducing apoptosis and DNA damage. The anti-proliferative effect was verified by MTT assay and colony formation assay. DNA double-stand breaks (DSBs) were obtained by observing the nuclear focus formation and the protein expression of γ-H2AX. Cell cycle arrest was evaluated by the cycle-related proteins such as CDK2, CDK4, CDK6, Cyclin D1 and P 21. Apoptosis was assessed by flow cytometry, mitochondrial membrane potential (MMP) detection and the expression of apoptosis-related proteins. Reactive oxygen species (ROS) generation was measured with 2′, 7′-dichlorofluorescein diacetate (DCFH-DA) staining. According to SAR analysis, the most potent compound 6a exhibited great inhibitory effect against A549 cells, which IC 50 value of 2.84 ± 0.68 μM. Furthermore, 6a remarkably induced DNA damage, cell cycle arrest and apoptosis in A549 cells. 6a treatment increased the levels of ROS. Network pharmacology and molecular docking predicted the potential signaling pathways and ligand-receptor interactions, and the results of western blotting showed that 6a inhibited the PI3K/Akt/Bcl-2 signaling pathway by decreasing PI3K and Bcl-2 and total level of Akt expression, while Bax and Cyt c were increasing in 6a -treated A549 cells. As mentioned above, 6a has a potent inhibitory effect in A549 cells through induction of DNA damage, apoptosis via ROS generation and modulation of PI3K/Akt/Bcl-2 signaling pathway.
研究领域:
药理学
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肿瘤学
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化学生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2021
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IF 3.196
Meng Ding,Lei Xu,Yumeng Zhang,Wei Li,Yuqing Zhao
20( R )-25-methoxyl-dammarane-3 β ,12 β ,20-triol (CN Patent: 201,010,107,476.7, AD-1) is a promising antitumor compound, was isolated from total hydrolyzed saponins extracted from Panax notoginseng leaves. A sensitive and rapid method for the simultaneous detection of AD-1 and its 8 major metabolites in rat feces was developed in this study. AD-1 (20 mg/kg) was orally administered to male rats by gastric intubation. Then, the feces samples were collected. After addition of internal standard (Mifepristone), feces samples were pretreated by protein precipitation followed by liquid-liquid extraction. Chromatographic separation was performed on an Angela C 18 column with gradient elution using a mobile phase composed of acetonitrile and water (containing 5 mM ammonium acetate) at a flow rate of 0.3 mL/min. The analytes were detected without any interference from the multiple reaction monitoring (MRM) mode using positive electrospray ionization. Calibration curves offered satisfactory linearity ( r > 0.995) within the determined ranges. Both intra-day and inter-day variances were lower than 15%, and the accuracy was within 85–115%. The fecal excretion recoveries of AD-1 (M0), metabolite 1 (M1), M2, M3, M4, M5, M6, M7 and M8 were 41.36%, 0.62%, 6.20%, 0.50%, 6.99%, 2.07%, 1.86%, 0.41% and 0.29%, respectively. The observed excretion profiles for AD-1 and its metabolites after oral administration are helpful to understand the poor oral bioavailability of AD-1, and will aid further investigations of AD-1 as a pharmacologically active component. Moreover, the in silico ADME (Absorption, Distribution, Metabolism, Excretion) predictions indicated that the metabolites were nontoxic and present passive gastrointestinal absorption. In previous studies, we found that M5, a metabolite of AD-1, has strong cytotoxicity against ovarian cancer cells. Further molecular docking studies showed that the most potent metabolite, M5, effectively binds to poly ADP-ribose polymerase-1 (PARP-1), which may provide novel solutions for treating ovarian cancer.
研究领域:
药理学
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药物代谢动力学
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计算生物学
✓ 已验证
产品关联
DOI
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2013
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IF 3.848
Lin-Hui Zhang,Yong-Liang Jia,Xi-Xi Lin,Hong-Quan Zhang,Xin-Wei Dong,Jun-Ming Zhao,Jian Shen,Hui-Juan Shen,Fen-fen Li,Xiao-Feng Yan,Wei Li,Yu-Qing Zhao,Qiang-Min Xie
Background Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug. Methods The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice. Results AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G 0 /G 1 cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger — N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10–40 mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index. Conclusions and general significance These data support development of AD-1 as a potential agent for lung cancer therapy.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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