- Design, synthesis and bioactivity evaluation of novel evodiamine derivatives with excellent potency against gastric cancer
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Gastric cancer represents a significant health burden worldwide. Previously, inspired by the traditional Chinese medicine Wu-Chu-Yu to treat the spleen and stomach system for thousands of years, we identified N14-phenyl substituted evodiamine derivatives as potential antitumor agents with favorable inhibition on Top1. Herein, structural optimization and structure-activity relationship studies (SARs) led us to discovering a highly active evodiamine derivative compound 6t against gastric cancer. Further anti-tumor mechanism studies revealed that compound 6t played as the inhibition of topoisomerase 1 (Top1), effectively induced apoptosis, obviously arrested the cell cycle at the G2/M phase, and significantly inhibited the migration and invasion of SGC-7901 and MGC-803 cell lines in a dose-dependent manner. Moreover, the compound 6t was low toxicity in vivo and exhibited excellent anti-tumor activity (TGI = 70.12%) in the MGC-803 xenograft models. In summary, compound 6t represents a promising candidate as a potential chemotherapeutic agent against gastric cancer.
- Liang, Ziyi,Lei, Fang,Deng, Jiedan,Zhang, Honghua,Wang, Yuqing,Li, Junfang,Shi, Tao,Yang, Xiaoyan,Wang, Zhen
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- Design, synthesis and bioactivity evaluation of novel N-phenyl-substituted evodiamine derivatives as potent anti-tumor agents
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Natural products are important sources for the development of therapeutic medicine, among which evodia fruit has a wide range of medicinal properties in traditional Chinese medicine. Evodiamine, the main active component of evodia fruit, has various anti-cancer effects and has been proved to be a Topo inhibitor. From our previous attempts of modifying evodiamine, we found that the N14 phenyl substituted derivatives had showed great anti-tumor activity, which prompted us to further explore the novel structures and activities of these compounds. Compound 6f, as a N14 3-fluorinated phenyl substituted evodiamine derivative, showed a certain inhibitory activity against Topo I at 200 μM. By studying its anti-tumor effects in vitro, compound 6f could inhibit proliferation and induce apoptosis, as well as arrest the cell cycle of HGC-27 and HT-29 cell lines at G2/M phase in a concentration-dependent manner. Moreover, compound 6f could inhibit the migration and invasion of HGC-27 cell lines. Meanwhile, compound 6f could induce apoptosis of HGC-27 cells by inhibiting PI3K/AKT pathway. Overall, this work demonstrated that the N14 phenyl-substituted evodiamine derivatives had a good inhibitory effect on tumor cells in vitro, providing a promising strategy for developing potential anticancer agents for the treatment of gastrointestinal tumors.
- Hao, Xiangyong,Deng, Jiedan,Zhang, Honghua,Liang, Ziyi,Lei, Fang,Wang, Yuqing,Yang, Xiaoyan,Wang, Zhen
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- Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma
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COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.
- Fan, Xiaohong,Li, Junfang,Long, Lin,Shi, Tao,Liu, Dan,Tan, Wen,Zhang, Honghua,Wu, Xiaoyan,Lei, Xiaoyong,Wang, Zhen
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- Tryptamine salicylic acid compound as well as preparation and application thereof
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The invention discloses a tryptamine salicylic acid compound which is characterized in that N-phenyl tryptamine salicylic acid (13) is used as a template molecule and is subjected to different modifications to obtain the tryptamine salicylic acid compound, the structural general formula of the tryptamine salicylic acid compound is shown in the description, or the invention discloses a novel N-phenyl tryptamine salicylic acid compound, the synthesis route of the compound is green and environment-friendly, simple and efficient, and raw materials are easy to obtain. In-vitro and in-vivo experiments prove that in-vitro anti-tumor activity shows that the compound shows good anti-human tumor activity, preferably glioma, has anti-tumor drug development potential, can be used for preparing anti-tumor drugs, provides a new thought for treatment of malignant glioma, and is beneficial to development of novel efficient and low-toxicity anti-glioma drugs.
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Paragraph 0016-0017
(2021/11/26)
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- Redox-neutral decarboxylative photocyclization of anthranilic acids
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A mild metal-, catalyst-, and oxidant-free photoredox neutral system has been found to efficiently enable intramolecular decarboxylative cyclization of anthranilic acids. This facile protocol provides an alternative method for the synthesis of carbazoles. Mechanistic studies reveal a key photoinduced 6π-electrocyclization process and formic acid was released as the sole byproduct.
- Huang, Huawen,Deng, Kun,Deng, Guo-Jun
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supporting information
p. 8243 - 8247
(2020/12/29)
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- Light-Driven Intramolecular C?N Cross-Coupling via a Long-Lived Photoactive Photoisomer Complex
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Reported herein is a visible-light-driven intramolecular C?N cross-coupling reaction under mild reaction conditions (metal- and photocatalyst-free, at room temperature) via a long-lived photoactive photoisomer complex. This strategy was used to rapidly prepare the N-substituted polycyclic quinazolinone derivatives with a broad substrate scope (>50 examples) and further exploited to synthesize the natural products tryptanthrin, rutaecarpine, and their analogues. The success of gram-scale synthesis and solar-driven transformation, as well as promising tumor-suppressing biological activity, proves the potential of this strategy for practical applications. Mechanistic investigations, including control experiments, DFT calculations, UV-vis spectroscopy, EPR, and X-ray single-crystal structure of the key intermediate, provides insight into the mechanism.
- Jing, Dong,Lu, Cong,Chen, Zhuo,Jin, Songyang,Xie, Lijuan,Meng, Ziyi,Su, Zhishan,Zheng, Ke
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supporting information
p. 14666 - 14672
(2019/09/06)
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- Improving the fluorescent probe acridonylalanine through a combination of theory and experiment
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Acridonylalanine (Acd) is a useful fluorophore for studying proteins by fluorescence spectroscopy, but it can potentially be improved by being made longer wavelength or brighter. Here, we report the synthesis of Acd core derivatives and their photophysical characterization. We also performed ab initio calculations of the absorption and emission spectra of Acd derivatives, which agree well with experimental measurements. The amino acid aminoacridonylalanine (Aad) was synthesized in forms appropriate for genetic incorporation and peptide synthesis. We show that Aad is a superior F?rster resonance energy transfer acceptor to Acd in a peptide cleavage assay and that Aad can be activated by an aminoacyl tRNA synthetase for genetic incorporation. Together, these results show that we can use computation to design enhanced Acd derivatives, which can be used in peptides and proteins.
- Sungwienwong, Itthipol,Ferrie, John J.,Jun, Joomyung V.,Liu, Chunxiao,Barrett, Taylor M.,Hostetler, Zachary M.,Ieda, Naoya,Hendricks, Amara,Muthusamy, Anand K.,Kohli, Rahul M.,Chenoweth, David M.,Petersson, George A.,Petersson, E. James
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supporting information
(2018/02/27)
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- Design and synthesis of some acridine-piperazine hybrids for the improvement of cognitive dysfunction
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A novel series of hybrid molecules (5a–5m) was designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against cognitive dysfunction. Heterocyclic moieties acridine and piperazine were conjugated with suitable linkers in a single scaffold, and the structures of the target compounds were confirmed by IR, 1H NMR, 13C NMR, and LC-MS analysis. The pharmacological activity of synthesized compounds was evaluated using behavioral models of amnesia viz. step-down passive avoidance and elevated plus maze at a dose 0.5?mg/kg as compared to standard rivastigmine. In vitro acetylcholinesterase (AChE) inhibition studies using brain homogenate of mice as the enzyme source revealed that most of the compounds exhibited a significant ability to inhibit the enzyme cholinesterase with compound 5c being the most potent (IC50 0.33?μm). Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase, and glutathione has been carried out using the respective assays to see the effect of the synthesized compounds on the scopolamine-induced oxidative damage. The molecular docking studies indicated the binding mode of the compounds to the catalytic site, peripheral site, and mid-gorge of AChE simultaneously. The calculated absorption, distribution, metabolism and excretion properties ensured the drug-likeness of the target compounds. The synthesized compounds were found to be potential cognitive enhancers, which were able to interfere with the scopolamine-induced oxidative stress also.
- Sharma, Anuradha,Piplani, Poonam
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p. 926 - 935
(2017/10/06)
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- Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety
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A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50= 1.21/2.15 nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure–activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.
- Tang, Qidong,Zhai, Xin,Tu, Yayi,Wang, Ping,Wang, Linxiao,Wu, Chunjiang,Wang, Wenhui,Xie, Hongbo,Gong, Ping,Zheng, Pengwu
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p. 1794 - 1798
(2016/12/22)
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- Potent acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivatives
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A novel series of acridone linked to 1,2,3-triazole derivatives have been synthesized and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The synthetic approach was started from the reaction of 2-bromobenzoic acid with aniline derivatives and subsequent cyclization reaction to give acridone derivatives. Then, reaction of the later compounds with propargyl bromide followed by azide-alkyne cycloaddition reaction (click reaction) led to the formation of the title compounds in good yields. Among the synthesized compounds, 10-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-methoxyacridin-9(10H)-one 9g, depicted the most potent anti-AChE activity (IC50 Combining double low line 7.31 μ1/4M). Also, docking study confirmed the results obtained through in vitro experiments and predicted possible binding conformation.
- Mohammadi-Khanaposhtani, Maryam,Saeedi, Mina,Zafarghandi, Narges Shamsaei,Mahdavi, Mohammad,Sabourian, Reyhaneh,Razkenari, Elahe Karimpour,Alinezhad, Heshmatollah,Khanavi, Mahnaz,Foroumadi, Alireza,Shafiee, Abbas,Akbarzadeh, Tahmineh
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p. 799 - 806
(2015/03/05)
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- Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9(10H-acridinone-1,2,3-triazoles
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A new series of 9(10H-acridinone-1,2,3-triazole derivatives were designed, synthesized and evaluated for their cytotoxic activity against human breast cancer cell lines. The acridone skeleton was prepared through the Ullman condensation of 2-bromobenzoic acid and anilines. Subsequently, it was functionalized with propargyl bromide. Then, a click reaction of the latter compound and in situ prepared 1-(azidomethyl)-4-methoxybenzene derivatives led to the formation of the desired triazole products. Finally, all products were investigated for their capability to cause cytotoxicity against MCF-7, T-47D, and MDA-MB-231 cell lines. Among them, 2-methoxy-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H-one 8c exhibited the most potency (hbox {IC}_{50},{=},11.0,{pm }, 4.8, upmu hbox {M})(IC50=11.0±4.8μM) against MCF-7 cells, being more potent than etoposide (hbox {IC}_{50},{=}, 12.4,{pm }, 4.7 upmu hbox {M})(IC50=12.4±4.7μM). Also, apoptosis induced by compound 8c was confirmed via acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide (PI) double staining.
- Mohammadi-Khanaposhtani, Maryam,Safavi, Maliheh,Sabourian, Reyhaneh,Mahdavi, Mohammad,Pordeli, Mahboobeh,Saeedi, Mina,Ardestani, Sussan Kabudanian,Foroumadi, Alireza,Shafiee, Abbas,Akbarzadeh, Tahmineh
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p. 787 - 795
(2015/10/12)
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