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Yang Y.,Tsinghua University | Shang P.,Tsinghua University | Cheng C.,Tsinghua University | Wang D.,Jiangsu Simcere Pharmaceutical Research Institute | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2010

A current study shows that sodium dichloroacetate (DCA) can induce cancer cell apoptosis and inhibit tumor growth, but its cytotoxic activity is low (IC50 > 1000 μM for A549). In this paper, a variety of DCA derivatives were synthesized, and their cytotoxic activities were evaluated. The result showed that the N-phenyl-2,2-dichloroacetamide analogues had satisfactory potencies. Among them, N-(3-iodophenyl)-2,2-dichloroacetamide (3e), an optimized lead compound, has an IC50 against A549 as low as 4.76 μM. Furthermore, it can induce cancer cell apoptosis and has a low toxicity in mice (LD50 = 1117 mg/kg). N-phenyl-2,2-dichloroacetamide analogues has higher cytotoxic activity and N-(3-iodophenyl)-2,2-dichloroacetamide (3e) is an optimized lead compound. © 2010 Elsevier Masson SAS. All rights reserved.

Zhu Y.,Jiangsu Simcere Pharmaceutical Research Institute | Wu G.,Jiangsu Simcere Pharmaceutical Research Institute | Zhu X.,Jiangsu Simcere Pharmaceutical Research Institute | Ma Y.,Jiangsu Simcere Pharmaceutical Research Institute | And 7 more authors.
Journal of Medicinal Chemistry | Year: 2010

An extensive structure-activity relationship (SAR) study of 72 dipeptidyl boronic acid proteasome inhibitors constructed fromβ -amino acids is reported. SAR analysis revealed that bicyclic groups at the R1 position, 3-F substituents at the R2 position, and bulky aliphatic groups at the R3 position were favorable to the activities. Enzymatic screening results showed that compound 78, comprising all of these features, was the most active inhibitor against the 20S human proteasome at less than a 2 nM level, as active as the marketed drug bortezomib. Cellular assays confirmed that compound 78 was the most potent against two hematologic and some solid tumor cells with IC50 values less than 1 μM. Pharmacokinetic profiles suggested that 78 showed higher plasma exposure and a longer half-life than bortezomib. © 2010 American Chemical Society.

Zhu Y.,Jiangsu Simcere Pharmaceutical Research Institute | Zhu X.,Jiangsu Simcere Pharmaceutical Research Institute | Wu G.,Jiangsu Simcere Pharmaceutical Research Institute | Ma Y.,Jiangsu Simcere Pharmaceutical Research Institute | And 11 more authors.
Journal of Medicinal Chemistry | Year: 2010

A series of novel dipeptidyl boronic acid proteasome inhibitors composed of β-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i was the most active. The IC50 value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC50 values nearly less than 5 μM against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in a similar way as bortezomib. © 2010 American Chemical Society.

Gao Q.,Tianjin University | Yang L.,Auriver Inc. | Zhu Y.,Jiangsu Simcere Pharmaceutical Research Institute
Current Computer-Aided Drug Design | Year: 2010

This review summarizes the background and updated progress of pharmacophore based drug design and provides the fundamental approach strategies on both structure based and ligand based pharmacophore approaches. The different programs and methodologies enable the implementation of more accurate and sophisticated pharmacophore model generation and application in drug discovery. This review will discuss and illustrate their advantages in pharmacophore based virtual screening and exemplify the detailed application workflow, which can be easily utilized by pharmaceutical bench work medicinal chemists. Pharmacophore based drug design process includes pharmacophore modeling and validation; pharmacophore based virtual screening, virtual hits profiling and lead identification. Strategies and proven methodologies for pharmacophore modeling are described including common feature and 3D QSAR based pharmacophore generation as well as structure based pharmacophore development. Different virtual screening strategies will be described in this review with detailed case studies for supporting practical applications. Representative success examples of pharmacophore based virtual screening for lead generation will be collected to demonstrate capabilities. © 2010 Bentham Science Publishers Ltd.

Lu J.,Tsinghua University | Cheng C.,Tsinghua University | Zhao X.,Jiangsu Simcere Pharmaceutical Research Institute | Liu Q.,Tsinghua University | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2010

Fifteen PEG-scutellarin prodrugs were synthesized by modifying carboxyl and phenolic hydroxyl groups of scutellarin with mPEG of different molecular weight (400-3000). The water solubility of prodrugs increased remarkably and reached the maximum value of 783.88 mg/mL (scutellarin, 0.02 mg/mL). The anti-infarct effects of four PEG prodrugs with high water solubility were evaluated by Cerebral Ischemia/Reperfusion in the Middle Cerebral Artery Occlusion (MCAO) model. The results showed that the prodrug 7e could significantly reduce the infarct area from 27.2% to 12.2% (33.3% for the control) and decrease the neurological deficit score from 2.77 to 1.32 (2.85 for the control). The half-life (18.62 min) of the prodrug 7e was significantly longer than that of scutellarin (3.03 min). © 2010 Elsevier Masson SAS. All rights reserved.

Li T.-W.,Tsinghua University | Yang Y.-C.,Tsinghua University | Cheng C.-M.,Tsinghua University | Wang D.-C.,Jiangsu Simcere Pharmaceutical Research Institute | And 2 more authors.
Yaoxue Xuebao | Year: 2012

Our earlier research has shown that mono-substituted N-phenyl-2, 2-dichloroacetamide exhibited much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this paper, a variety of multi-substituted N-phenyl-2, 2-dichloroacetamides were synthesized and biologically evaluated. The results showed that 3, 5-disubstituted N-phenyl-2, 2-dichloroacetamide analogues had satisfactory potency. Among them, N-(3,5-diiodophenyl)-2,2-dichloroacetamide had an IC50 of 2.84 μmol·L-1 against non-small cell lung cancer cell line A549 and could induce cancer cell apoptosis.

Yang P.,Tsinghua University | Kong X.,Academy of Military Medical science | Cheng C.,Tsinghua University | Li C.,Academy of Military Medical science | And 2 more authors.
Science China Chemistry | Year: 2011

Flavonoids are important bioactive dietary compounds, which are proved to be antioxidant responsive element (ARE) activators to defend against electrophilic toxicants and oxidative stress. The activators induce ARE gene transcription through Nrf2 factor, a major transcriptional stimulator of cytoprotective genes, relieved from a Keap1 complex. In this report, based on the structures of two flavonoids, scutellarin and baicalin, which are extracted from two common Chinese plants Dengzhanhua (Erigeron breviscapus (vant) Hand-Mazz) and Huangqin (Scutellaria baicalensis Georigi), respectively, we synthesized several 8-substituted and deglucuronidated analogues and identified the ARE activation effects of these flavonoids. We found that the Baicalin, deglucurnonidated Baicalin and diaza cyclopenta derivative were more active. Their dose-dependent upregulation activities of ARE and NQO1 and induction effects of Nrf2 were testified. The results presented that these three analogues had good upregulation effects on ARE, and they could be potentially utilized in relieving oxidative stress, upon further neuroprotective tests. © 2011 Science China Press and Springer-Verlag Berlin Heidelberg.

Xiao L.,Guangdong Medical College | Yang S.,Chinese University of Hong Kong | Yang S.,Wannan Medical College | Hao J.,Guangdong Medical College | And 8 more authors.
Cancer Letters | Year: 2015

To develop optimal therapeutics is one of the hotspots in both clinical and basic melanoma studies. Previous studies indicate that fibroblast growth factors (b-FGF/FGF-2), an angiogenesis inducer beyond VEGF, might be a potential drug target in melanoma. As a novel anti-angiogenesis peptide drug, Endostar has shown promising therapeutic efficacy in non-small cell lung cancer. However, the effect of Endostar on b-FGF-induced angiogenesis in melanoma is unraveled. To this end, both in vivo and in vitro experiments were conducted and it was found that treatment of Endostar could inhibit tumor growth, which was accompanied by decreased micro-vessel density and serum b-FGF levels in a mouse melanoma model. In addition, treatment with Endostar in blood vessel endothelial cells could reduce their proliferation, cell migration and tube formation capacity in a dosage-dependent manner. Moreover, treatment of Endostar could also attenuate b-FGF-activated phosphorylation of p38 and ERK1/2 in HUVECs. These findings indicate that Endostar might exert its anti-tumor effect via suppressing b-FGF-induced angiogenesis and b-FGF-activated MAPK signaling pathway, suggesting that Endostar might be a potential choice for clinical melanoma treatment. © 2015 Elsevier Ireland Ltd.

Jiang Z.-Y.,Nanjing University | Qin S.-K.,Nanjing University | Yin X.-J.,Jiangsu Simcere Pharmaceutical Research Institute | Chen Y.-L.,Jiangsu Simcere Pharmaceutical Research Institute | Zhu L.,Jiangsu Simcere Pharmaceutical Research Institute
Experimental and Therapeutic Medicine | Year: 2012

To explore an effective combination therapy for malignant ascites, the therapeutic value of the combination of Endostar, a modified recombinant human endostatin, and β-elemene, an active component of a traditional Chinese herb, in an H22 mouse malignant ascites model was investigated. The optimal dose combination of Endostar and β-elemene was determined by evaluating the inhibition of ascites volume and increase in the survival rate of the mice. Other therapeutic effects and the underlying mechanisms were investigated under the optimal dose combination (8 mg/kg Endostar plus 100 mg/kg β-elemene). The mice were randomly divided into four treatment groups and received intraperitoneal injection once a day for eight days: control (0.9% normal saline), Endostar (8 mg/kg), β-elemene (100 mg/kg) or optimal dose combination (8 mg/kg Endostar plus 100 mg/kg β-elemene), respectively. The results of this study revealed that the combination therapy had significant synergistic effects on the inhibition of ascites formation and a deceased number of tumor cells and protein levels in ascites compared with the results of treatment with a single agent. A decreased peritoneal microvascular permeability and reduction in VEGF, MMP-2 and hypoxia inducible factor 1α (HIF1α) was noted in the combination group, when compared with single agent treatment. These studies found that in the ascitic tumor cells, the protein levels of VEGF and MMP-2, as well as levels of VEGF mRNA, were significantly inhibited by the combination therapy. The potentiating effects of the combination of Endostar with β-elemene suggest that this novel therapy may yield an effective therapy for the treatment of malignant ascites.

Zheng Y.,China Pharmaceutical University | Gang W.,Jiangsu Simcere Pharmaceutical Research Institute | Zhu X.-R.,Jiangsu Simcere Pharmaceutical Research Institute | Li Y.-J.,Jiangsu Simcere Pharmaceutical Research Institute | And 4 more authors.
Chemical Research in Chinese Universities | Year: 2011

tert-Butyl (R)-3-amino-3-(3-fluorophenyl)propanoate(5) was prepared with conventional debenzylation method. However, the tert-butyl (R)-3-[(S)-1-phenylethyl-amino]-3-(3-fluorophenyl) propanoate(6) and tert-butyl (R)-3-amino-3-phenylpropanoate(7) were generated as the byproducts under the general catalytic hydrogenation Pd(OH)2/C-H2 conditions. So a series of experiments was performed to optimize the reaction conditions so that product 5 could be obtained with high purity and yield. Finally an effective catalytic system, Pd/C-HCOOH-CH3OH, was discovered.

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