Quantitation of sunitinib,an oral multitarget tyrosine kinase inhibitor,and its metabolite in urine samples by nonaqueous capillary electrophoresis time of flight mass spectrometry

A rapid, sensitive, and specific method was developed and validated using a nonaqueous‐capillary electrophoresis method with TOF‐MS for determination of sunitinib and N‐desethyl sunitinib in human urine. In order to avoid ionic suppression a urine samples dilution with methanol 1:10 previous step was used. This was the only treatment step to urine samples before the injection. Despite this dilution of the urine, the detection limit was as low as 0.07 mg/L for sunitinib and 0.15 mg/L for N‐desethyl sunitinib. Separation of compounds was achieved with a mixture of 5 mM ammonium formate in methanol. The calibration curves were linear over the range of 0.5–50.0 mg/L for the two analyzed compounds. The within‐run and between‐run precisions were within 5%, while the accuracy ranged from 96.0 to 100.4%. This method can be used in routine clinical practice to monitor sunitinib and N‐desethyl sunitinib drugs in the urine of cancer patients treated with once daily administration.     

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling,molecular docking, 3D-QSAR model and binding free energy calculation studies

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG_bind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC₅₀ < 50 μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs.     

Synthesis,crystal structure and activity evaluation of novel 3,4‐dihydro‐1‐benzoxepin‐5(2H)‐one derivatives as protein–tyrosine kinase (PTK) inhibitors

Four new 3,4‐dihydro‐1‐benzoxepin‐5(2H )‐one derivatives, namely (E )‐4‐(5‐bromo‐2‐hydroxybenzylidene)‐6,8‐dimethoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, ( 7 ), (E )‐4‐[(E )‐3‐(5‐bromo‐2‐hydroxyphenyl)allylidene]‐6,8‐dimethoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, ( 8 ), (E )‐4‐(5‐bromo‐2‐hydroxybenzylidene)‐6‐hydroxy‐8‐methoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, C₁₈H₁₅BrO₅, ( 9 ), and (E )‐4‐[(E )‐3‐(5‐bromo‐2‐hydroxyphenyl)allylidene]‐6‐hydroxy‐8‐methoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, ( 10 ), have been synthesized and characterized by FT–IR, NMR and MS. The structure of ( 9 ) was confirmed by single‐crystal X‐ray diffraction. Crystal structure analysis shows that molecules of ( 9 ) are connected into a one‐dimensional chain in the [010] direction through classical hydrogen bonds and these chains are further extended into a three‐dimensional network via C—H…O interactions. The inhibitory activities of these compounds against protein–tyrosine kinases (PTKs) show that 6‐hydroxy‐substituted compounds ( 9 ) and ( 10 ) are more effective for inhibiting ErbB1 and ErbB2 than are 6‐methoxy‐substituted compounds ( 7 ) and ( 8 ). This may be because ( 9 ) and ( 10 ) could effectively bind to the active pockets of the protein through intermolecular interactions.     

Molecular modeling study of checkpoint kinase 1 inhibitors by multiple docking strategies and prime/MM-GBSA calculation

Developing chemicals that inhibit checkpoint kinase 1 (Chk1) is a promising adjuvant therapeutic to improve the efficacy and selectivity of DNA-targeting agents. Reliable prediction of binding-free energy and binding affinity of Chk1 inhibitors can provide a guide for rational drug design. In this study, multiple docking strategies and Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA) calculation were applied to predict the binding mode and free energy for a series of benzoisoquinolinones as Chk1 inhibitors. Reliable docking results were obtained using induced-fit docking and quantum mechanics/molecular mechanics (QM/MM) docking, which showed superior performance on both ligand binding pose and docking score accuracy to the rigid-receptor docking. Then, the Prime/MM-GBSA method based on the docking complex was used to predict the binding-free energy. The combined use of QM/MM docking and Prime/MM-GBSA method could give a high correlation between the predicted binding-free energy and experimentally determined pIC(50) . The molecular docking combined with Prime/MM-GBSA simulation can not only be used to rapidly and accurately predict the binding-free energy of novel Chk1 inhibitors but also provide a novel strategy for lead discovery and optimization targeting Chk1.     

Analytical challenges and the development of biomarkers to measure and to monitor the effects of ocean acidification

Changing ocean-carbonate chemistry caused by oceanic uptake of anthropogenic atmospheric carbon dioxide leads to the formation of carbonic acid, thus lowering the pH of the sea with predictions of a decrease from current levels at 8.15 to 7.82 by the end of the century. The exact measurement of subtle pH changes in seawater over time presents significant analytical challenges, as the equilibrium constants are governed by water temperature and pressure, salinity effects, and the existence of other ionic species in seawater.Here, we review these challenges and how pH also affects dissolved inorganic and organic chemicals that affect biological systems. This includes toxic compounds (xenobiotics) as well as chemicals that are beneficial for marine organisms, such as the chemical signals (i.e. pheromones) that are utilized to coordinate animal behavior. We review how combining analytical, molecular and biochemical tools can lead to the development of biosensors to detect pH effects to enable predictive modeling of the ecological consequences of ocean acidification.     

Pharmacophore Modeling and in Silico Screening Studies to Design Potential KDR Kinase Inhibitors

A novel ligand‐based pharmacophore model for KDR kinase was generated on the basis of chemical features of 30 KDR kinase inhibitors. This pharmacophore model consists of one hydrogen‐bond acceptor, one hydrogen‐bond donor and two hydrophobic groups. Several methods have been used to validate the model, suggesting that it can serve as a reliable tool for virtual screening to facilitate the discovery of novel KDR inhibitors. The model was then used as database search query from the National Cancer Institute (NCI) database for the rational design to identify new hit compound.     

Theoretical studies on the conformational change of adenosine kinase induced by inhibitors

Adenosine kinase (AK) is a two‐domain protein that catalyzes the phosphorylation of adenosine to adenosine monophosphate. Inhibitors of AK could increase adenosine to levels that activate nearby adenosine receptors and produce a wide variety of therapeutically beneficial activities. To get insight into the interaction mechanism between inhibitors and AK, we chose two kinds of novel inhibitors, alkynylpyrimidine inhibitor (APy) and aryl‐nucleoside inhibitor (AN), and used docking and molecular dynamics simulation methods to study the conformational changes of human AK on binding inhibitors. The calculation results revealed that both APy and AN could induce conformational changes of AK and stabilize AK at different semiopen conformations. On binding APy, the small lid‐domain rotated 14°, and the binding pocket rearranged after MD simulation. But in AK‐AN complex, the rotation of small domain is 22°, and the sugar ring of AN is mobile in the binding pocket. Further docking calculations on APy analogues indicate that the semiopen conformation could well explain the SAR of AK inhibitors. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products

Lung cancer is one of the most common cancers and has a high mortality rate. Due to its high incidence, the clinical management of the disease remains a major challenge. Several reports have documented a relationship between the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway and lung cancer. The recognition of this pathway as a notable therapeutic target in lung cancer is mainly due to its central involvement in the initiation and progression of the disease. Interest in using natural and synthetic medications to target these signaling pathways has increased in recent years, with promising results in vitro, in vivo, and in clinical trials. In this review, we focus on the current understanding of PI3K/AKT/mTOR signaling in tumor development. In addition to the signaling pathway, we highlighted the therapeutic potential of recently developed PI3K/AKT/mTOR inhibitors based on preclinical and clinical trials.     

酪氨酸蛋白激酶抑制剂:亚苄基丙二腈类衍生物定量构效关系的量子化学研究

用量子化学从头算方法,对亚苄丙二腈衍生物的定量构效关系(QSAR)进行了研究,结果显示:指示变量I,偶极矩Dipole和最低空轨道的能量ELUMO对亚苄丙二腈衍生物的抑制活性有很大影响,回归分析得到了相关性好的相关模型(R=0.95).I=0时,亚苄基丙二腈类衍生物的抑制作用由其化学反应性决定;I=1时其抑制作用由其静电性决定.