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Huang W.,Central China Normal University | Huang W.,Jiangsu Simcere Pharmaceutical Co. | Chen Q.,Central China Normal University | Yang W.-C.,Central China Normal University | Yang G.-F.,Central China Normal University
European Journal of Medicinal Chemistry | Year: 2013

As widely occurring natural products, flavonoids are an important source for drug discovery, due to their structural diversity and broad-spectrum biological activity. In this work, a library of novel, thioethersubstituted flavonoids with diverse heterocyclic groups was synthesized via a microwave-assisted procedure with the advantages of good yields, short times, mild conditions and ready isolation of the products. Their antiproliferative activities were evaluated against six cancer cell lines, HCCLM-7, Hela, MDA-MB-435S, SW-480, Hep-2, and MCF-7 by the MTT-based assay. Compared with the positive control 5-fluorouracil, three compounds, 6a, 6b and 6j were successfully identified as the most promising candidates, due to their higher potency and broad-spectrum bioactivity with IC50 values in the range of 0.43 μM-6.7 μM. © 2013 Elsevier Masson SAS. All rights reserved.


Aa J.,China Pharmaceutical University | Shao F.,Jiangsu Simcere Pharmaceutical Co. | Wang G.,China Pharmaceutical University | Huang Q.,China Pharmaceutical University | And 10 more authors.
Metabolomics | Year: 2011

Metabolomics allows high-throughput analysis of low-molecular-weight compounds in biofluids that reflect the physiological status and biochemical metabolism of living systems. Hence it has the potential to evaluate toxicity and clarifies the metabolism-related toxic mechanisms. In this study a promising candidate drug parent, triptolide, was given to Sprague-Dawley rats as a model toxicant at a single dose of 0.6, or 2.4 mg/kg, i.g. Both routine biochemical assays and histopathological inspection showed time-dependent hepatic toxicity at the higher dose, but no obvious toxicity at the lower dose. Meanwhile, serum metabolome was profiled using the non-targeted metabolomic tool, gas chromatography time-of-flight mass spectrometry. Based on the acquired metabolomic data, mathematical models were calculated and the metabolic patterns of serum were evaluated using projection to latent structure-discriminant analysis. The relative distance of each treated group from the normal control was calculated to provide a measure of toxicity. Treatment with triptolide at either the higher or lower dose caused deviations in the metabolic pattern and resulted in perturbation of taurine, creatinine, free fatty acids, β-hydroxybutyrate, tricarboxylic acid cycle intermediates, and amino acids. This finding indicates the dysfunction of β-oxidation of free fatty acids and impairment of the mitochondria and confirms the hepatic toxicity of triptolide. The identified toxic markers and the calculated relative distance values quantitatively demonstrated dose- and time-dependent toxicity, whereas the scores plot of the model provided the qualitative information. The metabolomic approach was non-invasive and more sensitive than routine toxic assessment, and the results of both methods correlated well. © 2010 Springer Science+Business Media, LLC.


Zhao X.,China Pharmaceutical University | Zhao X.,Jiangsu Simcere Pharmaceutical Co. | Xin M.,Xian Jiaotong University | Jin Q.,Jiangsu Simcere Pharmaceutical Co. | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo. © 2014 Elsevier Ltd. All rights reserved.


Zhao X.,China Pharmaceutical University | Zhao X.,Jiangsu Simcere Pharmaceutical Co. | Huang W.,Jiangsu Simcere Pharmaceutical Co. | Huang W.,Central China Normal University | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

A series of novel reversible BTK inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2,3-d]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK enzyme (IC50 = 4.8 nM) and cellular inhibition (IC50 = 17 nM) assays to that of RN486. © 2014 Elsevier Ltd. All rights reserved.


Zhao X.,China Pharmaceutical University | Zhao X.,Jiangsu Simcere Pharmaceutical Co. | Xin M.,Xian Jiaotong University | Wang Y.,Jiangsu Simcere Pharmaceutical Co. | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

A novel series of BTK inhibitors bearing thieno[3,2-c]pyridin-4-amine framework as the core scaffold were designed, synthesized and well characterized. In this paper, twenty one compounds displayed variant inhibitory activities against BTK in vitro, and compound 14g showed the most potent inhibitory activity against BTK enzyme, with the IC50 value of 12.8 nM. Moreover, compounds 14g displayed relatively good kinase selectivity and was subsequently evaluated in vivo for profiling its PK properties. This work identified the thieno[3,2-c]pyridin-4-amine derivatives as novel BTK inhibitors and verified the value of thieno[3,2-c]pyridin-4-amine scaffold in drug design. © 2015 Published by Elsevier Ltd.

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