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A series of novel 2-aliphatic cyclic amine-3-(arylsulfonyl)quinoxalines was synthesized based on the structural features of a previously identified lead, WR1. The 2-piperidinol-3-(arylsulfonyl)quinoxalines, which showed excellent antitumor activities against five human cell lines, with inhibitory activities ranging from 0.34 to 2.32 μM, proved to be a promising class of novel PI3Kα inhibitors. The most potent compound 10d (WR23) showed an inhibitory IC(50) value of 0.025μM against PI3Kα and significant pAkt suppression effect. Molecular docking analysis was performed to determine possible binding modes between PI3Kα and target compounds., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A series of novel 2-arylamino-3-(arylsulfonyl)quinoxalines was synthesized through a newly developed approach. All synthesized target compounds were screened for their cytotoxicities against cancer cell lines including PC3, A549, HCT116, HL60 and KB. Representative compounds with favorable cytotoxicities were tested for their PI3Kα inhibitory activities. Among the synthesized target compounds, 17 (PI3Kα IC(50): 0.07 μM) displayed the most potent cellular activities (IC(50) values of 0.14 μM, 0.07 μM, 0.95 μM and 0.05 μM against PC3, A549, HCT116 and HL 60, respectively)., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A new series of 4 beta-anilino-podophyllotoxin analogs have been designed, synthesized and evaluated their bioactivities as novel DNA-topoisomerase II poisons as well as P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) inhibitors. The new compounds show improved potency and efficacy with respect to the parent molecule etoposide (VP-16), one of the semisynthetic derivatives of podophyllotoxin. The treatment of 5k-n in KB/VCR cells caused G(2)/M phase arrest and finally induced apoptosis. Furthermore, molecular docking is applied to testify that 5k-n could not be the substrates of P-gp, which is consistent with the result of MDR1 and P-glycoprotein express tests. The most potent compound 5n is chosen for in vivo studies, the administration of 5n was effective in treatment of cancer with a lower dose than VP-16 in drug-sensitive xenograft model and drug-resistant xenograft model. Compound 5n is a potential drug candidate for anticancer chemotherapy.

Background: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients.Methods: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation.Results: We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents.Conclusions: Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy. [ABSTRACT FROM AUTHOR]

Abstract: A total of 24 well-defined PKB/Akt1 inhibitors were used to generate pharmacophore models applying Catalyst/HypoGen program. The best ranked model (Hypo_1) was then validated by cost analysis, prediction capability, Cat-Scramble and receiver operating characteristic (ROC) studies. Then, pharmacophore-based virtual screening combined with docking study was performed to search an in-house compound database. Nine preferable hits 75–80, HTS-02143, BTB-14740 and HTS-08006 were prepared and biologically evaluated. Several compounds were identified as good PKB/Akt1 inhibitors, suggesting that Hypo_1 would be reliable and useful in virtual screening. Flow cytometric and western blotting analysis on compounds 79 and 80 further demonstrated that the inhibition of phosphorylation of PKB/Akt1 and its substrates (such as GSK3β) was responsible for their cytotoxic activities. [Copyright &y& Elsevier]

Abstract: A new series of flavonoid derivatives have been designed, synthesized and evaluated as potent AChE inhibitors. Most of them showed more potent inhibitory activities to AChE than rivastigmine. The most potent inhibitor isoflavone derivative 10d inhibit AChE with a IC50 of 4nM and showed high BChE/AChE inhibition ratio (4575-fold), superior to donepezil (IC50 =12nM, 389-fold). Molecular docking studies were also performed to explore the detailed interaction with AChE. [Copyright &y& Elsevier]

Abstract: A series of novel 7-azaindazolyl-indolyl-maleimides were synthesized and evaluated for their antiproliferative activity in vitro against various human cancer cell lines and protein kinase C inhibitory activity. Compounds 8a–c, 8e and 14a were the most promising compounds against K562, A549, ECA-109, KB and SMMC-7721 cell lines in vitro. Compounds 9a–j showed moderate PKC inhibition. Further mechanism of action studies revealed that the antiproliferative activity of compound 8b in KB cells might involve the mitochondria-mediated apoptosis pathway. [Copyright &y& Elsevier]

Abstract: BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO2 and ethanol, respectively. Ellman''s assay indicated BZYX exhibited high inhibition on AChE activity. IC50 values for BZYX: 0.058±0.022 μM; donepezil: 0.019±0.004 μM; rivastigmine: 3.81±2.81 μM; glantamine: 3.01±1.85 μM and huperzine A: 0.053±0.016 μM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H2O2) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 μM H2O2, while it significantly increased when the cells were pretreated with 0.1–1.0 μM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (ΔΨm), scavenged reactive oxygen species formation induced by H2O2 and resulted in up-regulation of procaspase3 and xIAP protein level and down-regulation of phosphorylated JNK protein, p53 protein level and cleavage of caspase 3. It is speculated that the mitochondrial pathway, mediated by Bcl-2 family and Mitogen-Activated Protein Kinases (MAPKs), might involved in the neuroprotection of BZYX. These results first demonstrated that BZYX had neuroprotective effects as well as cognition enhancement and acetylcholinesterase inhibition. It is hopeful that BZYX becomes a potential candidate for use in the intervention for neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: A new series of galanthamine derivatives have been designed, synthesized and evaluated as acetylcholinesterase inhibitors. All of the new compounds prepared showed high AChE inhibitory activities, with compound 3e that has an N-hexyl-benzyl piperidine substituent on the nitrogen atom reaching the best inhibitory activity for AChE (IC50 =5.62nM). The docking study performed with AutoDock demonstrated that 3e was nicely accommodated by AChE. [Copyright &y& Elsevier]

Abstract: A new series of indanone and aurone derivatives have been synthesized and tested for in vitro AChE inhibitory activity by modified Ellman method. Most of them exhibit AChE inhibitory activities superior to rivastigmine. Further, the most potent compound 1g was selected to evaluate the effect on the acquisition and memory impairment by mice step-down passive avoidance test. [Copyright &y& Elsevier]

Abstract: As a part of our project aimed at developing new agents of potential application in AD, a new series of 2-phenoxy-indan-1-one derivatives which possess alkylamine side chain were designed, synthesized, and evaluated for their inhibitory activity against AChE and BuChE. Most of the compounds were found to inhibit AChE in the nanomolar range. The optimum inhibitor 3g exhibited 34-fold increase in AChE inhibition than donepezil and displayed neuroprotective effect against H2O2-induced cell death. [Copyright &y& Elsevier]