Nanjing KeyGen Biotech. Co.

Nanjing, China

Nanjing KeyGen Biotech. Co.

Nanjing, China
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Huang Z.,China Pharmaceutical University | Fu J.,China Pharmaceutical University | Liu L.,China Pharmaceutical University | Sun Y.,Nanjing Keygen Biotech. Co. | And 5 more authors.
Organic and Biomolecular Chemistry | Year: 2012

A series of O2-glycosylated diazeniumdiolate-based derivatives of oleanolic acid (4-19) were synthesized and their anti-human hepatocellular carcinoma (HCC) activities were evaluated. Compound 6 selectively inhibited HCC, but not non-tumor liver cell proliferation. This inhibition was attributed to high levels of nitric oxide (NO) released in HCC cells. Importantly, 6 exhibited low acute toxicity (LD50 = 173.3 mg kg-1) and potent inhibition of HCC tumor growth in mice (3 mg kg-1 iv). Furthermore, 6 induced HCC cell apoptosis, which was accompanied by lower mitochondrial membrane potentials and Bcl2 expression, but with higher cytochrome C release, Bax, caspase 3 and 9 expression activities in HCC cells. Collectively, 6 may be a promising candidate drug for the intervention of HCC. © 2012 The Royal Society of Chemistry.


Li D.,China Pharmaceutical University | Xu S.,China Pharmaceutical University | Cai H.,China Pharmaceutical University | Pei L.,China Pharmaceutical University | And 7 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of enmein-type diterpenoid analogs (11-20) derived from natural kaurene-type diterpenoid oridonin were synthesized and biologically evaluated. All target compounds showed improved anti-proliferative activities against four human cancer cell lines compared with natural oridonin and parent compound 10. Some compounds were more potent than positive control Taxol. Furthermore, mechanistic investigation showed that the representative compound 17 affected cell cycle and induced apoptosis at low micro-molar level in human hepatoma Bel-7402 cells, via an oxidative stress triggered mitochondria-related caspase-dependent pathway. © 2013 Elsevier Masson SAS. All rights reserved.


PubMed | University of Kentucky, Nanjing KeyGen Biotech. Co. and China Pharmaceutical University
Type: | Journal: European journal of medicinal chemistry | Year: 2016

Inflammation plays a key role in cancer initiation and propagation. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two important enzymes in inflammatory responses are up-regulated in various tumor types. Dual inhibition of COX-2 and 5-LOX constitutes a rational concept for the design of more efficacious anti-tumor agents with an improved safety profile. We have previously reported a series of diaryl-1,2,4-triazole derivatives as selective COX-2 inhibitors. Herein, we hybridized the diaryl-1,2,4-triazoles with caffeic acid (CA) which was reported to display 5-LOX inhibitory and anti-tumor activities, affording a novel class of COX-2/5-LOX dual inhibitors as anti-tumor drug candidates. Most of these compounds exhibited potent COX-2/5-LOX inhibitory and antiproliferative activities invitro. And the most potent compound 22b could significantly inhibit tumor growth invivo. Furthermore, mechanistic investigation showed that the representative compound 15c blocked cell cycle in G2 phase and induced apoptosis in human non-small cell lung cancer A549 cells in a dose-dependent manner. Our preliminary investigation results would provide new clues for the cancer theatment with COX-2/5-LOX dual inhibitors.


Xu S.,China Pharmaceutical University | Pei L.,China Pharmaceutical University | Wang C.,China Pharmaceutical University | Zhang Y.-K.,St. John's University | And 7 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

A series of novel hybrids from natural product oridonin and nitrogen mustards were designed and synthesized to obtain more efficacious and less toxic antitumor agents. The antiproliferative evaluation showed that most conjugates were more potent than their parent compounds oridonin and clinically used nitrogen mustards against four human cancer cell lines (K562, MCF-7, Bel-7402, and MGC-803). Furthermore, the representative compounds 16a-c exhibited antiproliferative activities against the multidrug resistant cell lines (SW620/AD300 and NCI-H460/MX20). It was shown that the most effective compound 16b possesses a strong inhibitory activity with an IC50 value 21-fold lower than that of oridonin in MCF-7 cells and also exhibits selective cytotoxicity toward the cancer cells. Intriguingly, compound 16b has been demonstrated to significantly induce apoptosis and affect cell cycle progression in human hepatoma Bel-7402 cells. © 2014 American Chemical Society.


Bi Y.,Yantai University | Xu J.-Y.,China Pharmaceutical University | Sun F.,China Pharmaceutical University | Wu X.-M.,Jiangsu University | And 4 more authors.
Records of Natural Products | Year: 2013

A novel series of 17-carboxylic acid modified amide derivatives of 23-hydroxy betulinic acid (1) were prepared and tested in vitro against five cell lines: A549 (human lung carcinoma), BEL-7402 (human hepatoma), SF-763 (human cerebroma), B16 (mice melanoma) and HL-60 (human leukaemia). Within this series of compounds, 4a (IC50=21.08 μM in SF-763, IC50=21.63 μM in HL-60), 4b (IC50=28.45 μM in HL-60,IC50=29.32 μM in BEL-7402) and 6g (IC50=26.09 (μM in BEL-7402, IC50=22.65 (μM in HL-60) have the more potent cytotoxic activity than lead compound 1. The preliminary structure-activity relationship analysis of the C-28 amide derivatives is also discussed. © 2013 Reproduction is free for scientific studies.


Li D.,China Pharmaceutical University | Cai H.,China Pharmaceutical University | Jiang B.,China Pharmaceutical University | Liu G.,Shenyang Pharmaceutical University | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of novel spirolactone-type diterpenoid derivatives of oridonin (12a-j) were designed and synthesized. All the target compounds showed improved anti-proliferative activity against a panel of human cancer cell lines and the most effective compound 12j was more potent than positive control Taxol in K562 and Bel-7402 cells with IC50 values of 0.39 μM and 1.39 μM, respectively. The cellular mechanisms showed that compound 12j induced apoptosis at low micromolar concentrations in human hepatoma Bel-7402 cells. These results demonstrate that the spirolactone-type diterpenoid derivatives of oridonin have optimized growth inhibitory activity against cancer cells and interesting apoptosis-inducing ability.© 2012 Elsevier Masson SAS. All rights reserved.


Bi Y.,Yantai University | Xu J.,China Pharmaceutical University | Sun F.,China Pharmaceutical University | Wu X.,China Pharmaceutical University | And 3 more authors.
Molecules | Year: 2012

23-Hydroxybetulinic acid (1) served as the precursor for the synthesis of C-28 ester derivatives. The target compounds were evaluated in vitro for their antitumor activities against five cell lines (A549, BEL-7402, SF-763, B16 and HL-60). Among the obtained compounds, 6i had the most potent antitumor activity, with the IC 50 values of 8.35 μM in HL-60 cells and showed similar antitumor activity as cyclophosphamide in H22 liver tumor and as 5-fluorouracil in B16 melanoma in vivo.


PubMed | P.A. College, Nanjing University and Nanjing KeyGEN Biotech Co.
Type: Journal Article | Journal: Oncology reports | Year: 2015

Proanthocyanidins are flavonoids that are widely present in the skin and seeds of various plants, with the highest content in grape seeds. Many experiments have shown that proanthocyanidins have antitumor activity both in vivo and in vitro. Autophagy and apoptosis of tumor cells induced by drugs are two of the major causes of tumor cell death. However, reports on the effect of autophagy induced by drugs in tumor cells are not consistent and suggest that autophagy can have synergistic or antagonistic effects with apoptosis. This research was aimed at investigating whether proanthocyanidins induced autophagy and apoptosis in human gastric cancer cell line MGC-803 cells and to identify the mechanism of proanthocyanidins action to further determine the effect of proanthocyanidins-induced autophagy on apoptosis. MTT assay was used to examine the proanthocyanidin cytotoxicity against human gastric cancer cell line MGC-803. Transmission electron microscopy and monodansylcadaverine (MDC) staining were used to detect autophagy. Annexin V APC/7-AAD double staining and Hoechst 33342/propidium iodide (PI) double staining were used to explore apoptosis. Western blotting was used to determine expression of proteins related to autophagy and apoptosis. Real-time quantitative PCR technology was used to determine the mRNA level of Beclin1 and BCL-2. The results showed that proanthocyanidins exhibit a significant inhibitory effect on the human gastric cancer cell line MGC-803 proliferation in vitro and simultaneously activate autophagy and apoptosis to promote cell death. Furthermore, when proanthocyanidin-induced autophagy is inhibited, apoptosis increases significantly, proanthocyanidins can be used together with autophagy inhibitors to enhance cytotoxicity.


LI D.-H.,China Pharmaceutical University | WANG L.,China Pharmaceutical University | CAI H.,China Pharmaceutical University | JIANG B.-W.,China Pharmaceutical University | And 3 more authors.
Chinese Journal of Natural Medicines | Year: 2012

Aim: To search for novel nitric oxide (NO) releasing anti-tumor agents, a series of furoxan-based nitric oxide-releasing derivatives of 1-oxo-oridonin were designed and synthesized. Method: Different furozan-based NO donors (9a-i) were synthesized and conjugated with the 14-hydroxyl of 1-oxo-oridonin (2). The level of nitrate/nitrite in the cell lysates was tested by Griess assay and the anti-proliferative activity of these derivatives against four human cancer cell lines was also determined. Results: These furoxan-based NO-releasing derivatives could produce more than 19 μmol·L-1 of NO in vitro at the time point of 60 min. The most promising compound 10 h exhibited stronger activity than the positive control Taxol against the Bel-7402 cell line with an IC50 value 0.74 μmol·L-1. The structure-activity relationships were concluded based on the derived experimental data. Conclusion: These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents. © 2012 China Pharmaceutical University.


PubMed | P.A. College, Nanjing University and Nanjing KeyGen Biotech Co.
Type: Journal Article | Journal: Molecular medicine reports | Year: 2016

Diosgenin, a plant steroid compound from Dioscorea nipponica, is an anti-inflammatory, antidiabetic, antitumor, vasodilatory compound, which also reduces blood lipid content and protects against ischemiainduced neuronal damage. However, a limited number of studies have been performed on the antitumor effect of diosgenin on prostate cancer, the underlying mechanism of which remains to be fully elucidated. In the present study, the effect and underlying mechanism of diosgenin on DU145 human prostate cancer cells was investigated. DU145 cells were cultured invitro with diosgenin, following which cell proliferation was detected by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis was detected by flow cytometry. In addition, DU145 cells were observed under a transmission electron microscope to confirm autophagy. monodansylcadaverine staining and western blotting indicated the levels of autophagy in DU145 cells. To determine the mechanism underlying the effect of diosgenin on DU145 cells, western blotting was performed to evaluate the involvement of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. To investigate the association between apoptosis and autophagy, DU145 cells were cultured with diosgenin and 3methyladenine. Hoechst 33342/propidium iodide double staining was performed to detect apoptosis, and reverse transcriptionquantitative polymerase chain reaction was used to analyze mRNA expression levels of Beclin 1 and Bcell lymphoma 2. Diosgenin inhibits the proliferation of DU145 cells by activating apoptosis and autophagy, and the mechanism underlying this activation may be associated with the inhibition of the PI3K/Akt/mTOR signaling pathway. Inaddition, the inhibition of autophagy mediated by diosgenin increases apoptosis and, thus, increases the therapeutic effect. The combination of diosgenin with an autophagy inhibitor may be an effective strategy to increase the antitumor effect of diosgenin.

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