Showing papers by "Kaixian Chen published in 2011"

Utilization of Halogen Bond in Lead Optimization: A Case Study of Rational Design of Potent Phosphodiesterase Type 5 (PDE5) Inhibitors

Abstract: For proof-of-concept of halogen bonding in drug design, a series of halogenated compounds were designed based on a lead structure as new inhibitors of phosphodiesterase type 5. Bioassay results revealed a good correlation between the measured bioactivity and the calculated halogen bond energy. Our X-ray crystal structures verified the existence of the predicted halogen bonds, demonstrating that the halogen bond is an applicable tool in drug design and should be routinely considered in lead optimization.

Molecular basis of NDM-1, a new antibiotic resistance determinant.

Abstract: The New Delhi Metallo-β-lactamase (NDM-1) was first reported in 2009 in a Swedish patient. A recent study reported that Klebsiella pneumonia NDM-1 positive strain or Escherichia coli NDM-1 positive strain was highly resistant to all antibiotics tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now becomes potentially a major global health threat. In this study, we performed modeling studies to obtain its 3D structure and NDM-1/antibiotics complex. It revealed that the hydrolytic mechanisms are highly conserved. In addition, the detailed analysis indicates that the more flexible and hydrophobic loop1, together with the evolution of more positive-charged loop2 leads to NDM-1 positive strain more potent and extensive in antibiotics resistance compared with other MBLs. Furthermore, through biological experiments, we revealed the molecular basis for antibiotics catalysis of NDM-1 on the enzymatic level. We found that NDM-1 enzyme was highly potent to degrade carbapenem antibiotics, while mostly susceptible to tigecycline, which had the ability to slow down the hydrolysis velocity of meropenem by NDM-1. Meanwhile, the mutagenesis experiments, including D124A, C208A, K211A and K211E, which displayed down-regulation on meropenem catalysis, proved the accuracy of our model. At present, there are no effective antibiotics against NDM-1 positive pathogen. Our study will provide clues to investigate the molecular basis of extended antibiotics resistance of NDM-1 and then accelerate the search for new antibiotics against NDM-1 positive strain in clinical studies.

Iron deprivation suppresses hepatocellular carcinoma growth in experimental studies

Abstract: Purpose: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and iron overload is a significant risk factor in the development of HCC. In this study, we investigated the potential application of depriving iron by a novel iron chelator, thiosemicarbazone-24 (TSC24), in HCC treatment. Experimental Design: Two HCC cell lines and HFE knockout (HFE −/− ) mice were used to determine iron chelation efficiency of TSC24. The anticancer effects of TSC24 on HCC were analyzed in vitro and in athymic xenograft mouse models. Results: Treatment with TSC24 significantly decreased the cellular iron concentration in hepatoma cells and the serum iron concentration in HFE −/− mice by blocking iron uptake and interfering with normal regulation of iron levels. Moreover, the viability of HCC cell lines was reduced by TSC24. Confirming the mechanism of the agent, this decrease in viability could be partially rescued by addition of exogenous iron. TSC24 also suppressed tumor growth in athymic mice bearing human HCC xenografts in a concentration-dependent manner, without apparent toxicity in parallel with a decrease in the serum iron level. Further studies revealed that TSC24 efficiently triggered cell-cycle arrest and apoptosis in Hep3B and HepG2 cell lines. Conclusions: TSC24 is a potent iron chelator that suppresses human HCC tumor growth by disrupting iron homeostasis, reducing available iron, and triggering cell-cycle arrest and apoptosis, without apparent host toxicity at effective doses. Thus, TSC24 shows great potential for the treatment of HCC. Clin Cancer Res; 17(24); 7625–33. ©2011 AACR .

Application of nickel(II) complexes to the efficient synthesis of α- or β-amino acids.

Abstract: Nonproteinogenic α- or β-amino acids have attracted tremendous attention, as they are widely utilized for biological, biochemical, pharmaceutical, and asymmetric chemical investigations. Recently, we developed a series of new strategies for preparing achiral and chiral nickel(ii) complexes for the synthesis of amino acids. We applied these new methods utilizing chiral nickel(ii) complexes for the asymmetric Mannich reaction to synthesize enantiopure α,β-diamino acids, the enantioselective tandem conjugate addition-elimination reaction to prepare glutamic acid derivatives, the Suzuki coupling reaction to yield β(2)-amino acid derivatives, the asymmetric Mannich reaction to synthesize 3-aminoaspartate, the asymmetric Michael addition reaction to give β-substituted-α,γ-diaminobutyric acid derivatives, the asymmetric alkylation reaction to prepare linear ω-trifluoromethyl containing amino acids, and the asymmetric Michael addition reaction to synthesize syn-β-substituted tryptophans.

Discovering the distinct inhibitory effects between C4-epimeric glycosyl amino acids: new insight into the development of protein tyrosine phosphatase inhibitors.

Abstract: There has been increasing interest in the development of drug candidates based on sugar templates that possess rich structural and, especially, configurational diversities We disclose herein that the epimeric identity between methyl 3,4-bis-phenylalanyl/tyrosinyl triazolyl-alpha-D-galactopyranoside and glucopyranoside may lead to their distinct inhibitory effects on specific protein tyrosine phosphatases (PTPs) Subsequently performed molecular docking study elucidated the plausible binding behaviors of the more potent galactosyl inhibitors with their primary PTP target, ie Cell Division Cycle 25B (CDC25B) phosphatase

Fragment-based prediction of skin sensitization using recursive partitioning.

Abstract: Skin sensitization is an important toxic endpoint in the risk assessment of chemicals. In this paper, structure-activity relationships analysis was performed on the skin sensitization potential of 357 compounds with local lymph node assay data. Structural fragments were extracted by GASTON (GrAph/Sequence/Tree extractiON) from the training set. Eight fragments with accuracy significantly higher than 0.73 (p<0.1) were retained to make up an indicator descriptor fragment. The fragment descriptor and eight other physicochemical descriptors closely related to the endpoint were calculated to construct the recursive partitioning tree (RP tree) for classification. The balanced accuracy of the training set, test set I, and test set II in the leave-one-out model were 0.846, 0.800, and 0.809, respectively. The results highlight that fragment-based RP tree is a preferable method for identifying skin sensitizers. Moreover, the selected fragments provide useful structural information for exploring sensitization mechanisms, and RP tree creates a graphic tree to identify the most important properties associated with skin sensitization. They can provide some guidance for designing of drugs with lower sensitization level.

[Advances in the structure-activity relationship study of natural flavonoids and its derivatives].

Abstract: Flavonoids are a large class of compounds widely distributed in nature. Many pharmacological activities of flavonoids have been reported such as anti-cancer, antioxidant, anti-inflammatory, hepatoprotective, antithrombotic, vasodilator, antiviral, antibacterial, antiallergic, and so on. In recent years, domestic and foreign research groups choose natural flavonoids and optimize their chemical structures in order to develop a number of new derivatives with stronger pharmacological activities. As part of the mechanisms are not clear, we need to strengthen in-depth research in the SAR (structure-activity relationship) study for targeted and efficient structure optimization. This paper systematically summarize current researches in the SAR studies of flavonoids and their derivatives, which can serve as a reference for synthesizing new flavonoid derivatives.

Substituted-1H- indoles compound, method for preparing the same, application and pharmaceutical composition of the same

Abstract: The invention discloses a substituted-1H-indole compound with general formula as formula (I) and medically acceptable salt, solvent complex or hydrate, wherein Ar, R1, R2, n, X and Rx in the formula is defined as instruction; the compound has better prevention and cure action for experimental inflammation; the compound is dual inhibitor of epoxy oxygenase and 5-lipoxidas, which displays strong effective inhibitor for 5-lipoxidas; therefore the compound can be developed into safe non-steroidal anti-inflammatory agent to treat asthma, allergy and other immune disease and cardiovascular disease and/or prevention drug. The invention also provides the making method of the compound and its drug composition.

Synthesis of 4-Aryl-2(5H)-furanones by Gold(I)-Catalyzed Intramolecular Annulation

Abstract: A novel method that involves intramolecular annulation and a new type of rearrangement has been developed for the synthesis of 4-aryl-2(5H)-furanones. A variety of prop-2-ynyl 3-oxo-3-phenylpropanoates undergo annulation cyclization in the presence of chloro(triphenylphosphine)gold and trifluoromethanesulfonic to afford the desired products in moderate to high yields.

Synthesis of 4-Aryl-2(5H)-furanones by Gold(I)-Catalyzed Intramolecular Annulation.

Abstract: The title reaction is carried out under mild conditions and shows excellent tolerance to various functional groups.