Publications by authors named "Dong-Jun Fu"

27 Publications

  • Page 1 of 1

Annual review of LSD1/KDM1A inhibitors in 2020.

Eur J Med Chem 2021 Mar 3;214:113254. Epub 2021 Feb 3.

School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China. Electronic address:

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising target for the discovery of specific inhibitors as antitumor drugs. Based on the source of compounds, all LSD1 inhibitors in this review are divided into two categories: natural LSD1 inhibitors and synthetic LSD1 inhibitors. This review highlights the research progress of LSD1 inhibitors with the potential to treat cancer covering articles published in 2020. Design strategies, structure-activity relationships, co-crystal structure analysis and action mechanisms are also highlighted.
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http://dx.doi.org/10.1016/j.ejmech.2021.113254DOI Listing
March 2021

Discovery of novel indole derivatives that inhibit NEDDylation and MAPK pathways against gastric cancer MGC803 cells.

Bioorg Chem 2021 02 8;107:104634. Epub 2021 Jan 8.

School of Basic Medical Science, Zhengzhou University, Zhengzhou 450001, China; The Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, Jiangsu, China. Electronic address:

A series of novel indole derivatives were synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (MGC803, EC-109 and PC-3). Among these analogues, 2-(5-methoxy-1H-indol-1-yl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (V7) showed the best inhibitory activity against MGC803 cells with an IC value of 1.59 μM. Cellular mechanisms elucidated that V7 inhibited colony formation, induced apoptosis and arrested cell cycle at G2/M phase. Importantly, indole analogue V7 inhibited NEDDylation pathway and MAPK pathway against MGC803 cells.
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http://dx.doi.org/10.1016/j.bioorg.2021.104634DOI Listing
February 2021

Ras/Raf/MEK/ERK pathway axis mediated neurotoxicity induced by high-risk pesticide residue-Avermectin.

Environ Toxicol 2021 May 31;36(5):984-993. Epub 2020 Dec 31.

Zhengzhou Fruit Research Institute, Chinese Academy of Agricultural Sciences, Zhengzhou, China.

Pesticide residues have become a healthy threaten of human beings. Among the pesticides, many of them have neurotoxicity. Extracellular Regulated Protein Kinases (ERK) pathway is an important signaling pathway that regulates a variety of downstream progress. In this work, peach (PRUNUS persica) and cherry (PRUNUS cerasus) were sampled from over 300 plantations in China and assessed for the residue risk. In mechanism studies, high-risk pesticide Avermectin showed a high activity inhibiting three neurotoxicity models, SH-SY5Y, PC-12 and SK-N-SH cells. At protein levels, ERK pathway proteins and their downstream proteins were obviously down-regulated. Moreover, the effects of low-dose Avermectin can be accumulated at protein levels in the low-dose long-term chronic toxicology detection.
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http://dx.doi.org/10.1002/tox.23086DOI Listing
May 2021

Discovery of tertiary amide derivatives incorporating benzothiazole moiety as anti-gastric cancer agents in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.

Eur J Med Chem 2020 Oct 13;203:112618. Epub 2020 Jul 13.

Institute of Drug Discovery & Development, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China. Electronic address:

On the basis and continuation of our previous studies on anti-tubulin and anti-gastric cancer agents, novel tertiary amide derivatives incorporating benzothiazole moiety were synthesized and the antiproliferative activity was studied in vitro. Preliminary structure activity relationships (SARs) were explored according to the in vitro antiproliferative activity results. Some of compounds could significantly inhibit the proliferation of three cancer cells (HCT-116, MGC-803 and PC-3 cells) and compound F10 exhibited excellent antiproliferative activity against HCT-116 cells (IC = 0.182 μM), MGC-803 cells (IC = 0.035 μM), PC-3 cells(IC = 2.11 μM) and SGC-7901 cells (IC = 0.049 μM). Compound F10 effectively inhibited tubulin polymerization (IC = 1.9 μM) and bound to colchicine binding site of tubulin. Molecular docking results suggested compound F10 could bind tightly into the colchicine binding site of β-tubulin. Moreover, compound F10 could regulate the Hippo/YAP signaling pathway. Compound F10 activated Hippo signaling pathway from its very beginning MST1/2, as the result of Hippo cascade activation YAP were inhibited. And then it led to a decrease of c-Myc and Bcl-2 expression. Further molecular experiments showed that compound F10 arrested at G2/M phase, inhibited cell colony formatting and induced extrinsic and intrinsic apoptosis in MGC-803 and SGC-7901 cells. Collectively, compound F10 was the first to be reported as a new anticancer agent in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.
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http://dx.doi.org/10.1016/j.ejmech.2020.112618DOI Listing
October 2020

β-Lactams as promising anticancer agents: Molecular hybrids, structure activity relationships and potential targets.

Eur J Med Chem 2020 Sep 23;201:112510. Epub 2020 Jun 23.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China. Electronic address:

β-Lactam, commonly referred as azetidin-2-one, is a multifunctional building block for synthesizing β-amino ketones, γ-amino alcohols, and other compounds. Besides its well known antibiotic activity, this ring system exhibits a wide range of activities, attracting the attention of researchers. However, the structurally diverse β-lactam analogues as anticancer agents and their different molecular targets are poorly discussed. The purpose of this review is 3-fold: (1) to explore the molecular hybridization approach to design β-lactams hybrids as anticancer agents; (2) the structure activity relationship of the most active anticancer β-lactams and (3) to summarize their antitumor mechanisms.
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http://dx.doi.org/10.1016/j.ejmech.2020.112510DOI Listing
September 2020

Novel piperidine derivatives as colchicine binding site inhibitors induce apoptosis and inhibit epithelial-mesenchymal transition against prostate cancer PC3 cells.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1403-1413

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Tubulin polymerisation inhibitors that target colchicine binding site were powerful anticancer agents. Although along the years many colchicine binding site inhibitors (CBSIs) have been reported, few piperidine derivatives were identified as CBSIs. In this regard, we focussed efforts on the piperidine as a promising chemotype to develop potent CBSIs. Herein, novel piperidine derivatives were synthesised and evaluated for their antiproliferative activities. Among them, compound displayed powerful anticancer activity with the IC value of 0.81 µM against PC3 cells, which was significantly better than 5-fluorouracil. It could inhibit tubulin polymerisation binding at the colchicine site and inhibit the tumour growth and . Further biological studies depicted that suppressed the colony formation, induced apoptosis, and inhibited epithelial-mesenchymal transition against PC3 cells. These results revealed that compound is a promising colchicine binding site inhibitor for the treatment of cancer and it is worthy of further exploitation.
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http://dx.doi.org/10.1080/14756366.2020.1783664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646549PMC
December 2020

Antiproliferative benzothiazoles incorporating a trimethoxyphenyl scaffold as novel colchicine site tubulin polymerisation inhibitors.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1050-1059

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Tubulin polymerisation inhibitors exhibited an important role in the treatment of patients with prostate cancer. Herein, we reported the medicinal chemistry efforts leading to a new series of benzothiazoles by a bioisosterism approach. Biological testing revealed that compound could significantly inhibit tubulin polymerisation of a concentration dependent manner, with an IC value of 2.87 μM. Immunofluorescence and EBI competition assay investigated that compound effectively inhibited tubulin polymerisation and directly bound to the colchicine-binding site of β-tubulin in PC3 cells. Docking analysis showed that formed hydrogen bonds with residues Tyr357, Ala247 and Val353 of tubulin. Importantly, it displayed the promising antiproliferative ability against C42B, LNCAP, 22RV1 and PC3 cells with IC values of 2.81 μM, 4.31 μM, 2.13 μM and 2.04 μM, respectively. In summary, compound was a novel colchicine site tubulin polymerisation inhibitor with potential to treat prostate cancer.
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http://dx.doi.org/10.1080/14756366.2020.1753721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178834PMC
December 2020

Discovery of novel tertiary amide derivatives as NEDDylation pathway activators to inhibit the tumor progression in vitro and in vivo.

Eur J Med Chem 2020 Apr 28;192:112153. Epub 2020 Feb 28.

School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China.

NEDDylation pathway regulates multiple physiological process, unlike inhibitors, NEDDylation activators are rarely studied. Novel amide derivatives were synthesized and evaluated for antiproliferative activity against MGC803, MCF-7 and PC-3 cells. Among them, Ⅶ-31 displayed the most potent activity with an IC value of 94 nmol/L against MGC803 cells. Cellular mechanisms elucidated that Ⅶ-31 inhibited the cell viability, arrested cell cycle at G2/M phase and induced apoptosis via intrinsic and extrinsic pathways against MGC803 cells. In addition, Ⅶ-31 activated NAE1-Ubc12-Cullin1 NEDDylation via interacting with NAE1 directly. Furthermore, the activation of NEDDylation resulted in the degradation of inhibitor of apoptosis proteins (IAPs). Importantly, Ⅶ-31 inhibited tumor growth in xenograft models in vivo without the apparent toxicity. In summary, it is the first time to reveal that Ⅶ-31 deserves consideration for cancer therapy as a NEDDylation activator.
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http://dx.doi.org/10.1016/j.ejmech.2020.112153DOI Listing
April 2020

Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy.

Mol Carcinog 2020 02 29;59(2):193-201. Epub 2019 Nov 29.

Department of Urology, University of California, Irvine, California.

Gartanin, a 4-prenylated xanthone, has been identified from the purple mangosteen fruit as a potent growth inhibitor of various cancer cell lines, including prostate cancer. However, much of Gartanin's anticancer mechanism remains unknown. We have discovered that Gartanin docked onto the regulatory subunit of the precursor cell-expressed developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) complex and next to the NEDD8 binding complex, which leads to inhibit NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 NEDDylation in an in vitro assay. The S phase kinase-associated protein (Skp2) and F-box and WD-repeat domain-containing 2 (FBXW2), the NEDD8 family members of E3 ubiqutin ligases, were also downregulated and upregulated by Gartainin, respectively. Knock-down of NEDD8 expression by short harpin (Sh) RNAs blocked or attenuated these effects of Gartainin. Finally, Gartanin demonstrated its ability to inhibit growth of prostate cancer lines via autophagy initiation. Our data support that Gartanin is a naturally occurring NEDDylation inhibitor and deserves further investigation for prostate cancer prevention and treatment.
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http://dx.doi.org/10.1002/mc.23140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946862PMC
February 2020

Discovery of indoline derivatives that inhibit esophageal squamous cell carcinoma growth by Noxa mediated apoptosis.

Bioorg Chem 2019 11 10;92:103190. Epub 2019 Aug 10.

School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

A series of novel indoline derivatives were synthesized and evaluated for antiproliferative activity against four selected cancer cell lines (Hela, A549, HepG2 and KYSE30). Among them, compound 20 displayed the potent inhibition activity against esophageal cancer cells (Kyse30, Kyse450, Kyse510 and EC109). Cellular mechanism studies in esophageal squamous cell carcinoma (ESCC) cells elucidated compound 20 inhibited cell growths in vitro and in vivo, reduced colony formation, arrested cell cycle at M phase, and induced Noxa-dependent apoptosis in ESCC. Importantly, compound 20 was identified as a novel Noxa mediated apoptosis inducer. These results suggested that compound 20 might be a promising anticancer agent with potential for development of further clinical applications.
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http://dx.doi.org/10.1016/j.bioorg.2019.103190DOI Listing
November 2019

Corrigendum to "Synthesis and preliminary antiproliferative activity of new pteridin-7(8H)-one derivatives" [Eur. J. Med. Chem. 143 (2018) 1396-1405].

Eur J Med Chem 2019 Nov 31;181:111387. Epub 2019 Jul 31.

Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.ejmech.2019.05.077DOI Listing
November 2019

Discovery of novel chalcone-dithiocarbamates as ROS-mediated apoptosis inducers by inhibiting catalase.

Bioorg Chem 2019 05 16;86:375-385. Epub 2019 Jan 16.

School of Basic Medical Science, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

Novel chalcone-dithiocarbamate hybrids were designed, synthesized and evaluated for antiproliferative activity against selected cancer cell lines (MGC803, MCF7, and PC3). Among these analogues, (E)-2-oxo-2-((4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)amino)ethyl-4-(2-hydroxyethyl)piperazine-1-carbodithioate (12d) showed the best inhibitory activity against PC3 cells (IC = 1.05 μM). Cellular mechanism studies elucidated 12d could inhibit colony formation, arrest cell cycle at G2/M phase and induce DNA damage against PC3 cells. Compound 12d also induced mitochondrial apoptosis by caspase activation, MMP decrease, ROS production and catalase (CAT) inhibition. Importantly, 12d inhibited epithelial-mesenchymal transition (EMT) process by regulating EMT-related proteins (E-cadherin, N-cadherin, Vimentin, MMP2, MMP9). These results indicated that 12d is a promising lead compound and deserves further investigation for prevention and treatment of human prostate cancer.
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http://dx.doi.org/10.1016/j.bioorg.2019.01.023DOI Listing
May 2019

Molecular diversity of trimethoxyphenyl-1,2,3-triazole hybrids as novel colchicine site tubulin polymerization inhibitors.

Eur J Med Chem 2019 Mar 18;165:309-322. Epub 2019 Jan 18.

School of Basic Medical Science, Zhengzhou University, Zhengzhou, 450001, China; The Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001, China; Henan Institutes of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China. Electronic address:

Structurally diverse trimethoxyphenyl-1,2,3-triazole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three cancer cell lines (PC3, MGC803 and HepG2). Among them, trimethoxyphenyl-1,2,3-triazole containing the coumarin fragement 19c displayed better antiproliferative activity results with IC50 values from 0.13 μM to 1.74 μM than anticancer drug colchicine. Compound 19c could inhibit MGC803 cell growth and colony formation, induce G2/M phase arrest by down expression of CDK1, and promote apoptosis by regulating DR5 and Bcl-2 family. Moreover, 19c strongly inhibited tubulin polymerization by interacting with the colchicine site.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.033DOI Listing
March 2019

Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor.

Bioorg Chem 2019 03 16;84:164-169. Epub 2018 Nov 16.

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou 450001, PR China. Electronic address:

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.
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http://dx.doi.org/10.1016/j.bioorg.2018.11.018DOI Listing
March 2019

Mechanisms of synergistic neurotoxicity induced by two high risk pesticide residues - Chlorpyrifos and Carbofuran via oxidative stress.

Toxicol In Vitro 2019 Feb 30;54:338-344. Epub 2018 Oct 30.

Zhengzhou Fruit Research Institute China Chinese Academy of Agricultural Sciences, Zhengzhou 450009, China; Henan Key Laboratory of Fruit and Cucurbit Biology, Zhengzhou 450009, China. Electronic address:

Multi-component pesticide residues, especially pesticide residues with synergistic toxicity, are a serious threat to food safety. With risk assessment, we found that Chlorpyrifos (CPF) and Carbofuran (CBF) are 2 pesticide residues with highest risk for Actinidia chinensis planch. The results showed CPF and CBF have a synergistic neurotoxicity on neural cell SK-N-SH. The toxicity was partly depending on oxidative stress (OS) and had effects on cell apoptosis and cell cycle arrest. Furthermore, the toxicity remained on long-term low-dose condition.
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http://dx.doi.org/10.1016/j.tiv.2018.10.016DOI Listing
February 2019

Bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment exerting potent antiproliferative activity through microtubule destabilization.

Eur J Med Chem 2018 Sep 29;157:50-61. Epub 2018 Jul 29.

School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

Novel bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment as antiproliferative agents by targeting tubulin were synthesized and their preliminary structure activity relationships (SARs) were explored. Among all these chemical agents, 2-(Benzo[d]oxazol-2-ylthio)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (4d) exhibited the potent antiproliferative activity against MGC-803 cells with an IC value of 0.45 μM by induction of G2/M pahse arrest and cell apoptosis. In addition, 4d could change the membrane potential (ΔΨ) of the mitochondria against MGC-803 cells. Importantly, 4d acted as a novel tubulin polymerization inhibitor binding to colchicine site with an IC value of 3.35 μM.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.060DOI Listing
September 2018

Design, synthesis and preliminary biological evaluation of 5,8-dihydropteridine-6,7-diones that induce apoptosis and suppress cell migration.

Eur J Med Chem 2018 Jan 5;143:1959-1967. Epub 2017 Nov 5.

Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China. Electronic address:

Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells.
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http://dx.doi.org/10.1016/j.ejmech.2017.11.009DOI Listing
January 2018

Synthesis and preliminary antiproliferative activity of new pteridin-7(8H)-one derivatives.

Eur J Med Chem 2018 Jan 16;143:1396-1405. Epub 2017 Oct 16.

Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address:

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8H)-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7H-purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established.
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http://dx.doi.org/10.1016/j.ejmech.2017.10.037DOI Listing
January 2018

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site.

Sci Rep 2017 10 6;7(1):12788. Epub 2017 Oct 6.

School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China.

We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.
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http://dx.doi.org/10.1038/s41598-017-12912-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630639PMC
October 2017

Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors.

Molecules 2017 Sep 5;22(9). Epub 2017 Sep 5.

School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl--((1-(3-phenoxybenzyl)-1-1,2,3-triazol-4-yl)methyl)benzenesulfonamide () showed the most potent inhibitory effect against PC-3 cells, with an IC value of 4.08 μM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound was 2.41 μM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents.
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http://dx.doi.org/10.3390/molecules22091470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151726PMC
September 2017

Molecular diversity of phenothiazines: design and synthesis of phenothiazine-dithiocarbamate hybrids as potential cell cycle blockers.

Mol Divers 2017 Nov 7;21(4):933-942. Epub 2017 Aug 7.

New Drug Research and Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.

Novel phenothiazine-dithiocarbamate analogues were designed by molecular hybridization strategy and synthesized and evaluated for their anticancer activity in vitro against three selected cancer cell lines (EC-109, MGC-803, and PC-3). The preliminary structure-activity relationship (SAR) for this phenothiazine-dithiocarbamate hybrids is explored. Among all analogues, 2-oxo-2-(10H-phenothiazin-10-yl)ethyl 4-ethylpiperazine-1-carbodithioate (8a) showed the most potent inhibitory activity with an [Formula: see text] value of [Formula: see text] against PC-3 cells. In addition, compound 8a could arrest the cell cycle at the G1 phase and regulate the expression of G1 checkpoint-related proteins, suggesting that phenothiazine-dithiocarbamate hybrids might be useful as cell cycle blockers.
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http://dx.doi.org/10.1007/s11030-017-9773-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975273PMC
November 2017

Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers.

Eur J Med Chem 2017 Sep 8;138:1076-1088. Epub 2017 Jul 8.

New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China. Electronic address:

A series of 5,6-diaryl-1,2,4-triazines hybrids bearing a 1,2,3-triazole linker were synthesized by molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, EC-109 and PC-3). The first structure-activity relationship (SAR) for these 5,6-diaryl-1,2,4-triazines is explored in this report with evaluation of 15 variants of the structural class. Among these chemical derivatives, 3-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5,6-diphenyl-1,2,4-triazine (11E) showed the more potent inhibitory effect against three cell lines than 5-Fu. Cellular mechanism studies in MGC-803 cells elucidated 11E inhibited colony formation and arrested cell cycle at G2/M phase. Furthermore, compound 11E caused morphological changes, decreased mitochondrial membrane potential, and induced apoptosis through the apoptosis-related proteins in MGC-803 cells. It was the first time, to our knowledge, that 5,6-diaryl-1,2,4-triazines bearing a 1,2,3-triazole linker were used as potential apoptosis inducers.
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http://dx.doi.org/10.1016/j.ejmech.2017.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975277PMC
September 2017

Identification of thiazolo[5,4-d]pyrimidine derivatives as potent antiproliferative agents through the drug repurposing strategy.

Eur J Med Chem 2017 Jul 22;135:204-212. Epub 2017 Apr 22.

Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address:

A series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activities on three cancer cell lines. The structure-activity relationship studies were conducted through the variation in the three regions of the thiazolo-pyrimidine core. Substitution with morpholine led to compound 24, which exerted the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC values of 1.03 μM against MGC803 and 38.95 μM against GES-1). In addition, compound 24 inhibited the colony formation and migration of MGC803 as well as induced apoptosis. Western blot experiments indicated the expression changes of apoptosis-related proteins, including up-regulation of Bax and caspase-3/9, as well as down-regulation of Bcl-2.
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http://dx.doi.org/10.1016/j.ejmech.2017.04.056DOI Listing
July 2017

Design and synthesis of formononetin-dithiocarbamate hybrids that inhibit growth and migration of PC-3 cells via MAPK/Wnt signaling pathways.

Eur J Med Chem 2017 Feb 14;127:87-99. Epub 2016 Dec 14.

School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert-butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (8i) showed the best inhibitory activity against PC-3 cells (IC = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567725PMC
February 2017

Design, synthesis and antiproliferative activity studies of novel dithiocarbamate-chalcone derivates.

Bioorg Med Chem Lett 2016 08 5;26(16):3918-22. Epub 2016 Jul 5.

Collaborative Innovation Center of New Drug Research and Safety Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.

A series of novel dithiocarbamate-chalcone derivates were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell lines (EC-109, SK-N-SH and MGC-803). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds II2 and II5 exhibited the excellent growth inhibition against SK-N-SH with IC50 values of 2.03μM and 2.46μM, respectively. Further mechanism studies revealed that compound II2 could obviously inhibit the proliferation of SK-N-SH cells by inducing apoptosis and arresting the cell cycle at G0/G1 phase.
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http://dx.doi.org/10.1016/j.bmcl.2016.07.012DOI Listing
August 2016

Design, Synthesis and Structure-Activity Relationships of Novel Chalcone-1,2,3-triazole-azole Derivates as Antiproliferative Agents.

Molecules 2016 May 19;21(5). Epub 2016 May 19.

Collaborative Innovation Center of New Drug Research and Safety Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.

A series of novel chalcone-1,2,3-triazole-azole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, EC-109 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound I-21 showed the most excellent antiproliferative activity with an IC50 value of 1.52 μM against SK-N-SH cancer cells. Further mechanism studies revealed that compound I-21 induced morphological changes of SK-N-SH cancer cells possibly by inducing apoptosis. Novel chalcone-1,2,3-triazole-azole derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating neuroblastoma.
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http://dx.doi.org/10.3390/molecules21050653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274517PMC
May 2016

Efficient three-component one-pot synthesis of steroidal polysubstituted anilines.

Steroids 2015 Dec 22;104:1-7. Epub 2015 Jul 22.

School of Pharmaceutical Sciences of Zhengzhou University and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, No. 100, KeXue DaDao, Zhengzhou 450001, PR China. Electronic address:

An efficient and practical base-promoted cascade reaction has been developed to access steroidal polysubstituted anilines from simple precursors. The protocol reported herein achieved the formation of a benzene ring as well as three continuous C-C bonds in a single operation. The reaction mechanism was proposed on the basis of the key intermediate obtained. Besides, this method could be potentially employed for the synthesis of biphenyl compounds. The adjacent amine and nitrile groups existed in the final products have the potential for late stage functionalization, which would provide efficient access to steroidal compound collections with structural diversity and complexity.
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http://dx.doi.org/10.1016/j.steroids.2015.07.005DOI Listing
December 2015
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