Friday, September 30, 2016

BSP Journal: Letters in Drug Design & Discovery New Issue Launched!

In Vitro and In Vivo Investigations into the Carbene Copper Bromide Anticancer Drug Candidate WBC4

Author(s): Wolfgang Walther, Iduna Fichtner, Frauke Hackenberg, Wojciech Streciwilk and Matthias Tacke
Affiliation: UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.


The anticancer drug candidate 1,3-di(p-methoxybenzyl)-4,5-di(p-isopropylphenyl)-imidazol-2-ylidene copper( I) bromide (WBC4) was tested on the NCI 60 cancer cell panel in vitro. WBC4 showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with an average GI50 value of 288 nM. This encouraged maximum tolerable dose (MTD) experiments in mice, where a MTD value of 10 mg/kg was determined with single injections to groups of 2 mice. In the following tumor xenograft experiment WBC4 was given at 5 and 10 mg/kg in 5 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. At the higher dose of 10 mg/kg WBC4 showed borderline toxicity leading to 2 mortalities, while a significant T/C value of 0.38 was observed on day 32. At the lower dose of 5 mg/kg WBC4 induced mild and reversible body weight loss with no toxic deaths. At this dose WBC4 showed an identical significant T/C value of 0.38 on day 32, when compared to the treatment group. Immunohistochemistry for the proliferation marker Ki-67 did not show significant changes due to WBC4 treatment in the animals. However, anti-angiogenic effects by WBC4 treatment were observed in CD31 immunohistochemistry. Here, significant reduction in microvessel number, area and ratio was determined in tumors treated with 10 mg/kg of WBC4.

Synthesis and Biological Evaluation of New Pyrazole-based Thiazolyl Hydrazone Derivatives as Potential Anticancer Agents

Author(s): Mehlika Dilek Altıntop, Ahmet Ozdemir, Sinem Ilgın and Ozlem Atli
Affiliation: Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskisehir, Turkey.


New pyrazole-based thiazolyl hydrazone derivatives were obtained via the ring closure reaction of 3,5- dimethyl-1H-1-phenylpyrazole-4-carboxaldehyde thiosemicarbazone with 2-bromoacetophenone derivatives. The compounds were investigated for their cytotoxic effects on A549 and NIH3T3 cell lines. Among these compounds, compound 2i bearing a trifluoromethyl substituent can be identified as the most promising anticancer agent against A549 cancer cell lines. Compound 2i exhibited its inhibitory effect on A549 cells with an IC50 value of 0.0316 mM, whereas cisplatin showed its anticancer activity with an IC50 value of 0.01 mM. According to the IC50 values, the inhibitory effect of compound 2i on A549 cells can be considered to be selective when compared with its effect on NIH3T3 cells.

Synthesis and Anticancer Activity of 2,4,5-triaryl Imidazole Derivatives

Author(s): Fatemeh Elahian, Morteza Akbari, Maryam Ghasemi, Neda Behtooee, Mohaddeseh Taheri and Mohsen Amini
Affiliation: Department of Medicinal Chemistry Research and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.


This study describes the synthesis of four 2,4,5-triarylimidazole derivatives and their anticancer activities. The target compounds were prepared from the reaction of benzaldehyde and benzoin derivatives in presence of ammonium acetate and ammonium vanadate. All the synthesized compounds were screened for anticancer activities against T47D and MDA-MB231 cell lines using the MTT assay. However, our obtained results indicated a significant difference between colchicines cytotoxicity and their homologs on treated MDA-MB231 and T47D cells; one compound (4a) showed a significant IC50 on MDA-MB231 cells in cell culture assay.

Synthesis and Bioactivity of Novel Carvacrol and Thymol Derivatives Containing 5-Phenyl-2-furan

Author(s): Zining Cui, Xinghai Li and Yoshihiro Nishida
Affiliation: Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Department of Plant Pathology, College of Natural Resource and Environment, South China Agricultural University, Guangzhou 510642, China.


A series of novel carvacrol and thymol derivatives containing 5-phenyl-2-furan were synthesized. The antitumor tests showed that the title compounds exhibited promising activity against Bel-7402 and KB. The fungicidal tests showed that most of the title compounds had a considerable effect on the selected fungi. Generally the bioactivity of the carvacrol and its derivatives were better than that of the thymol and its derivatives. The substituted groups on the orthoand para- positions gave better activity than that of ones on the meta-position.

Investigating the Contributions of Residues to Dipeptidyl Peptidase-IV Inhibitor Binding by Molecular Dynamics Simulation

Author(s): Mengyuan Liu, Xun Sun and Xian Zhao
Affiliation: State Key Laboratory of Crystal Materials, Shandong University, Jinan 250100, China.


Dipeptidyl peptidase-IV (DPP-IV) is well known to be an attractive therapeutic target to treat type II diabetes. The aim of this work is to determine the residues which make great contributions to inhibitor binding by comparing the interactions between different inhibitors and residues in DPP-IV. To achieve this, two DPP-IV/inhibitor complexes were studied by molecular dynamics simulations. Hydrogen bond and interaction energy analysis were then carried out. The results indicate that several residues could make great contributions to inhibitor binding. Medicinal chemists may have priority to choose these residues to form strong non-bonded interactions with designed compounds. It is hoped that this work could help medicinal chemists to design more potent DPP-IV inhibitors.

Identification of Potential MEK1 Inhibitors by Pharmacophore-based Virtual Screening and MD Simulations

Author(s): Huanhuan Shi, Lu Zhou, Guangkai Bao, Qianying Yi, Suwen Zhou, Yahui Tian and Xiaoli Li
Affiliation: College of Chemical Engineering, Sichuan University, Sichuan, Chengdu, 610065, China.


MEK proteins play a critical role in tumor proliferation, differentiation, and survival. Hence MEK1 inhibitors are of particular importance in the treatment of related diseases. The present study describes pharmacophore-based 3DQSAR model generation based on 82 known inhibitors of MEK1 allosteric binding cavity. The best pharmacophore model developed consisted of four features, namely AHHR. The model was used as a query to screen the databases of almost 1.3 million compounds. Finally, 8 hits were indentified and the docking study manifested that these compounds interacted with MEK1 well. Finally, 10 ns MD simulations of the obtained ligand-receptor system were performed. The stable binding mode of the system was determined. Our results showed that the identified 8 hits would be useful for the development of potent MEK1 agents.

4’-Modified Pyrimidine Nucleosides as Potential Anti-hepatitis C Virus (HCV) Agents

Author(s): Neeraj Shakya, Satish Vedi, Chao Liang, Babita Agrawal and Rakesh Kumar
Affiliation: Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, Canada T6G 2S2.


Herein, we have investigated novel pyrimidine nucleosides bearing a 4’-carboxyl functionality (6-10, 13 and 15) as anti-HCV agents. In this new class of compounds, 7, 9, 10 and 15 demonstrated in vitro anti-HCV activity similar to or better than a known anti-HCV drug, ribavirin. In this work, we also, surprisingly, identified a 3’-sulfoxide analog of 3’-thiacytidine (16), obtained as a side product during the synthesis of 15, as a potent inhibitor of HCV replication at the concentration similar to that of ribavirin. No detectable in vitro cytotoxicity was observed for the investigated compounds up to the highest concentration tested.
courtesy by : Bentham Insight



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