Based on ninety three acetylcholinesterase inhibitors (AChEIs) which have the same mechanism of action but are different in structural characteristics, the pharmacophore model for acetylcholinesterase inhibitor was constructed by the CATALYST system. The optimal pharmacophore model with three hydrophobic units, a ring aromatic unit and a hydrogen-bond acceptor unit were confirmed (Weight=3.29, RMS=0.53, total cost-null cost=62.75, Correl=0.93, Config=19.05). This pharmacophore model will act on the double active site of acetylcholinesterase and is able to predict the activity of known acetylcholinesterase inhibitors that are used for clinical treatment of Alzheimer's disease (AD), and can be further used to identify structurally diverse compounds that have higher activity treating with Alzheimer's disease (AD) by virtual screening.

Objective By virtual screening in MDL,to search for a novel γ-secretase inhibitor.Methods A series of compounds were designed,synthesized,and evaluated based on pharmacophore model of γ-secretase inhibitors by virtual screening in MDL.Results The drug-likeness analytic data synthesized indicated that target compounds had drug-likeness.Each svnthesized compound was checked by IR spectroscopy,~1H and ~(13)C-NMR spectroscopy.Conclusion The designed compounds had better activity by model prediction.And the optimal compound showed a significant estimated activity value of 0.025 nmol/L and can be used as a lead for further drug development.

Ras/Raf/MEK/ERK singal transduction plays an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolism. This investigation focused on this signal pathway and chose farnesyl transferase (FTase) as the main target and Raf-1 kinase as the second target. A lot of compounds were selected to construct the pharmacophore models of farnesyl transferase inhibitors (FTIs) and Raf-1 kinase inhibitors by using computer-aided drug design (CADD). The pharmacophore of FTIs is constituted by a hydrogen bonding acceptor, an aromatic ring, a positive ionizable and two hydrophobic regions; the pharmacophore of Raf-1 kinase is constituted by a hydrogen donor, a hydrogen acceptor, a hydrophobic regions and an aromatic ring. There are some similarities between the two pharmacophores. After analysis of the constructions of these two pharmacophores, some new aminomethylbenzoic acid derivatives with good forecasting activity against both of FTase and Raf-1 kinase were designed with these new pharmacophore models.

The reduce of bioactivity and augment of the side effect of single-target drugs is generated by the multi-factorial properties of the pathogenesis of disease, which could be solved by the multi-target drugs. The problems and its solution of the design of the multi-target drugs were discussed in this paper, at the same time, the design of the multi-target drugs by pharmacophore model method is presented.
Computer-Aided Design ; Drug Combinations ; Drug Delivery Systems ; methods ; Drug Design ; Humans ; Signal Transduction ; drug effects

Multi-target drugs attract increasing attentions for the therapy of complicated neurodegenerative diseases. In this study, a computer-assisted strategy was applied to search for multi-target compounds by the pharmacophore matching. This strategy has been successfully used to design dual-target inhibitor models against both the acetylcholinesterase (AChE) and poly (ADP-ribose) polymerase-1 (PARP-1). Based on two pharmacophore models matching and physicochemical properties filtering, one hit was identified which could inhibit AChE with IC50 value of (0.337 +/- 0.052) micromol x L(-1) and PARP-1 by 24.6% at 1 micromol x L(-1).

The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin (NVC), N-maleoyl- glycine-curcumin (NGC) were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6 - 24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial (HKC) cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 micromol/L - 40 micromol/L NVC and NGC for 6 - 24 h, the growth inhibitory effects on EJ cells were 6.71% - 65.13% (P < 0.05), 10.96% - 73.01% (P < 0.05), respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased (P < 0.01). It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumor-targeted chemotherapeutic drugs.
Antineoplastic Agents, Phytogenic/*pharmacology ; Curcumin/*pharmacology ; Dose-Response Relationship, Drug ; Prodrugs/*chemical synthesis ; Prodrugs/*pharmacology ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/*pathology

AIMTo investigate the inhibitory effect of 2-aminothiazole derivatives on Neuro-cell apoptosis and QSAR.

METHODSThe 2-aminothiazole derivatives were designed and synthesized based on the lead compound of PFT-alpha, the protective action of the compounds I and II against and their inhibitory action on PC12 cell apoptosis induced by H2O2 were determined by MTT method and FCM method. The QSAR equation was obtained from Cerius2-QSAR+ module.

RESULTSEleven novel 2-aminothiazole Schiff base compounds (II) have been designed and synthesized. The structure of the compound II were characterized by IR, MS,1H NMR, 13C NMR. Their protective action against and the inhibitory action on PC12 cell apoptosis induced by H2O2 were found in this experiment. The optimal QSAR equation obtained from the Cerius2-QSAR+ module by using log (1/EC50) with corresponding descriptors is Activity = 6.947 68 - 0.088 72 x "LUMO" - 0.043 018 x "Alogp98" - 0.128 752 x "Rad0fGration" + 0.018 246 x "Dipole-mag". The correlation statistics parameters of the above equation are as follows: r2 = 0.970, F-test = 49. 149, r = 0. 985 and Lse = 0. 001.

CONCLUSIONThe 2-aminothiazole derivatives exhibited certain activity in inhibiting PC12 cell apoptosis induced by H2O2. Some compounds such as I-6, I-9 and II-6 have the dual activities, the protective action against and inhibitory action on PC12 cell apoptosis induced by H2O2. The QSAR equation indicated that it is favorable for enhance the activity of 2-aminothiazole derivatives by the reduction of "radius of gyration" and the energy of "LUMO" of the compounds.

Animals ; Apoptosis ; drug effects ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Drug Design ; Hydrogen Peroxide ; pharmacology ; Molecular Structure ; Neuroprotective Agents ; chemical synthesis ; pharmacology ; PC12 Cells ; Quantitative Structure-Activity Relationship ; Rats ; Thiazoles ; chemical synthesis ; chemistry ; pharmacology

Objective To clone and identify the differentially expressed genes of rat intestinal epithelial cell line (IEC 6) before and after exposure to high dose radiation so as to provide proof for the investigation of the molecular mechanisms in the repair of radiation damage of intestinal epithelial cells. Methods A subtractive cDNA library for differentially expressed genes was constructed by suppression subtractive hybridization (SSH) and T/A cloning technique after IEC 6 cells were exposed to radiation at the dose of 35 Gy ? ray. The expressed sequence tag (EST) library was screened by reverse Northern hybridization. Positive clones were sequenced and the similarity was searched against the DNA database in GenBank. Limited clones were identified by Northern hybridization. Results More than 2 000 white clones were harvested after the library amplification. Ninety six of them were randomly picked out for PCR amplification, and 15 positive clones which corresponded to 12 individual genes were identified by reverse Northern hybridization. These genes were involved in cell skeleton, cell stress, cell cycle control, and signal transduction, etc. In addition, a novel cDNA sequence was also obtained. Conclusion A subtractive cDNA library for differentially expressed genes in IEC 6 cells exposed to the radiation at the dose of 35 Gy ? ray has been successfully constructed with SSH and T/A clone techniques. Several positive ESTs which correspond to genes involving in cell skeleton, cell stress, cell cycle control, and signal transduction are identified. These genes may play important roles in the process of the damage and repair of the intestinal epithelial cells exposed to radiation.

The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin (NVC), N-maleoyl- glycine-curcumin (NGC) were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6-24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial (HKC) cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 μmol/L- 40 μmol/L NVC and NGC for 6 - 24 h, the growth inhibitory effects on EJ cells were 6.71% -65.13 % (P＜0.05), 10.96 % -73.01% (P ＜0.05), respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased (P＜0.01). It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumortargeted chemotherapeutic drugs.