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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.

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.

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.

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.

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.

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