Letters in Drug Design & Discovery - Volume 8, Issue 4, 2011

The 4-diethylaminomethylbenzyl-substituted titanocene dichloride (Titanocene Y*), which is completely water- soluble and showed nanomolar activity against the human renal cancer cells CAKI-1, was tested in vitro in an antiangiogenesis assay against human umbilical vein endothelial cells, HUVEC, delivering an IC50 value of 23 +/- 17 μM. Titanocene Y* was then given at 25, 50 and 75 mg/kg/d, on five consecutive days per week for up to three weeks to one cohort of six CAKI-1 tumor-bearing female NMRI:nu/nu mice, while a further cohort was treated with solvent only. At the two higher dosages Titanocene Y* showed high toxicity leading to mortality, while the titanocene-treated mouse cohort treated with the lowest dosage showed a moderate but statistically significant tumor growth reduction with respect to the solvent-treated control group, with an optimal T/C value of 76% at the end of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced by 21%. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 23% due to Titanocene Y* treatment. The substance caused dose-dependent body weight loss but did not reduce the number of white blood cells at doses of 25 and 50 mg/kg/d.

A series of coumarinyl chalcones derivatives were synthesized and evaluated for their antiproliferative activities on three different breast cancer cell lines (MDA-MB231, MDA-MB468, MCF7) and one non-cancer breast epithelial cell line (184B5). The coumarinyl derivatives exhibited anticancer activity against breast cancer cell lines at a micromolar range. A structure-activity relationship (SAR) analysis was performed by studying the effect of substituents on their antiproliferative activities. One of the compound 3i bearing methoxy substitutions at the R1, R2 and R3 positions of the phenyl ring showed comparable potency to the reference drug cisplatin as well as a two-fold higher selectivity for the breast cancer cell lines than 184B5 cells.

Four (6,7-dimethoxy-2-oxo-2H-chromen-4-yl)methyl 3-arylacrylate (5a-d) analogues of the antitumor agent (6,7-dimethoxy-2-oxo-2H-chromen-4-yl)methyl 3-(4-methoxyphenyl)acrylate (2) were synthesized. The compounds 5a-d have one or two nitrogen atoms incorporated on the aryl moiety, and therefore could be converted into hydrochloride salts (6a-d) and these salts possess greater water solubility compared to 2. Antitumor activity evaluation of using BDF1 mice bearing 3LL tumor cells model demonstrated significant inhibitory effects of compounds 6a-d against tumor growth with inhibition rates from 37.2 to 48.2%.

Quinoxaline-2, 3-dione obtained from cyclocondensation reaction of o-phenylene diamine with oxalic acid, was reacted with chlorosulphonic acid under cold condition followed by a reaction with various benzimidazoles to give 2, 3- dioxo-1, 2, 3, 4-tetrahydroquinoxaline-6-sulphonyl benzimidazoles in satisfactory yield. Their structures were confirmed using 1H NMR, IR and mass analysis. Cytotoxicity of these derivatives were evaluated by growth inhibition of HEp-2 cells in vitro. The preliminary bioassay indicated that these compounds showed moderate cytotoxicity.

Purpose: Vagus Nerve Stimulation (VNS) is indicated in the treatment of pharmacoresistant epilepsy. Albeit its general efficacy, the use of VNS remains undefined concerning two points: i) there are only a few long-term studies, none randomized; ii) there are no clinical markers which allow to predict VNS response. In order to explore these points, we report the long-term outcomes of VNS in 22 patients. Methods: Twenty-two patients with refractory epilepsy, either symptomatic generalized or cryptogenic/symptomatic partial were treated with VNS and monitored up to 15 years (6.5±1.1). Results: No significant adverse events were observed. VNS efficacy was enduring and increased significantly over time. Seizure frequency decreased by 34.3±3.9% after 1 year, 40.3±4.6% after 2 years, 48.0±5.4% after 3 years, 53.4±7.9% after 5 years and 48.1%±5.8 at maximum follow up. Data on syndrome-specificity were not significant (small number of patients in each group). Conclusions: This study confirms sustained efficacy of VNS in epilepsy. Generalized symptomatic and temporal lobe epilepsy seem to be associated to a better outcome to VNS, but additional data are required.

A novel synthetic procedure for a series of 4-Aryl-3-phenyl-6,7,8,9-tetrahydro- benzothieno[3,2- f][1,4]oxazepin-5(4H)-one 8a-s derivatives had been described. Six compounds 8a,b,h,j,m,s were selected and submitted to pharmacological evaluation for anxiolytic activity in the open field test. All the test compounds except 8b significantly reduced the exploratory activity and the emotionality of the rats in the open-field. These inhibitory results are in agreement with the effect of reference standard chlorpromazine as a tranquillizer and anxiolytic in the same conditions.

The mammalian target of rapamycin (mTOR) has become an attractive target for the treatment of cancer. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies was performed on a series of 4- morpholinopyrrolopyrimidine derivatives and used to identify the most important features impacting their activity and their potential for predictability. The CoMFA and CoMSIA models using 31 molecules in the training set, gave r2 cv values of 0.832 and 0.815, r2 values of 0.969 and 0.951, respectively. Furthermore, the external validation was applied and indicated that our CoMFA and CoMSIA models were robust enough to predict the activities of test compounds with rpred 2 values of 0.975 and 0.968, r02 values of 0.971 and 0.972, rm2 values of 0.926 and 0.813, respectively. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Molecular docking was used to investigate the binding mode between these compounds and the receptor and furthermore, verify the reliability of the 3D-QSAR models. The information obtained from molecular modeling studies helped in understanding the structure-activity relationship of these compounds and served as a useful guide for the design of 4-morpholinopyrrolopyrimidine derivatives with desired activity. Thus a set of new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models.

Apoptosis, the programmed cell death, is a highly organized process essential for elimination of degenerated cells. Therefore, a tremendous effort is put into the development of new cancer therapeutics, which induce apoptosis in tumor cells. The integration of novel computer-based strategies, which accelerate this development, is a challenging goal. In this context, a variety of terphenyl-based compounds that mimic the alpha-helical region of the pro-apoptotic Bak BH3 domain has already been identified. These compounds were used as lead compounds for an in silico screening in our database which contains more than four million drug-like molecules. During this screening, the compounds from the virtual database were compared with the lead compounds by 2D and 3D similarities. After additional property filtering and docking experiments, five promising candidates have been validated in vitro experiments to strengthen the in silico results.

Lymphatic Filariasis is a dreadful disease of mankind that infects more than one billion people worldwide. It is mainly caused by the nematode worms Wuchereria bancrofti, Brugia malayi and Brugia timori. Antifilarial agents that can kill all the stages in the life cycle of causative filariae are yet to be developed. Trehalose phosphatase is one of the key enzymes that plays a vital role in trehalose metabolism important for egg hatching of the Brugia malayi nematode. Interestingly, absence of similar protein in human makes this enzyme a potential drug target. As the structure of this enzyme has not been experimentally determined, a 3-Dimensional model of the target was generated by remote homology modeling. Since the magnesium ion is required for the structural integrity and enzymatic activity of the target protein, predicted model was therefore complexed with magnesium and docking studies were carried out. The lead compounds which competitively bind to this class of alpha-glucosidase family of enzymes, and thereby inhibit their activity were selected. With the generated model, an induced fit docking study was performed using Schrodinger supported GLIDE. The docking results indicated the conserved residues to be involved in antagonist binding and that the lead compounds could be used in designing anti-filarial drugs.

We report in this work the antimalarial activity of N-dodecyl-ethylenediamine (NDEDA). This compound was tested in vivo in a Plasmodium berghei murine model using the 4-day suppressive test in two separate experiments and displayed a very good inhibition of parasite multiplication.

A number of new derivatives of monoterpenoid with a para-menthane framework 3-methyl-6-(prop-1-en-2- yl)cyclohex-3-ene-1,2-diol (-)-3 were synthesized. The antiviral activity of (-)-3 and its derivatives against the pandemic influenza virus A/California/07/09 (H1N1)v was studied in vitro. Compound (-)-3 was found to be active against this virus (selectivity index 7.5); for mononicotinate (+)-6 the selectivity index was 17. The absolute configuration of compound 6 was shown to be critical for its antiviral activity.

The effective management of the cutaneous herpes simplex virus infections with acyclovir sodium (ACV) is limited due to reduced availability of ACV at the basal epidermis. The present research focused to improve the transcutaneous permeation of ACV from carbopol gels with different chemical permeation enhancers (dimethylsulfoxide, dlimonene, sodium taurodeoxycholate). The ex-vivo permeation was carried out using excised rat abdominal skin. The extent of ACV accumulated in the rat skin layers was also estimated and found to be higher with gel based formulations compared to reference formulation. Further, the irritancy test and histological studies were carried out to understand the mechanism of ACV permeation across stratum corneum. The improvement in the transcutaneous permeation assessed from steady state flux, permeability coefficient and enhancement ratio were significantly enhanced with gel formulations compared to reference formulation. In conclusion, research findings reveal the potential of carbopol gels for maximizing the therapeutic benefit in herpes virus infections.

Lipid peroxidation is the oxidative modification of polyunsaturated fatty acids (PUFA) that leads to hydroperoxides. Hydroperoxides that are derived from the lipid arachidonic acid serve as regulators of the enzymes involved in prostaglandin synthesis. Further oxidation of these hydroperoxides produces short chain aldehydes, such as 4- hydroxynonenal. The mechanism of lipid peroxidation is well established, yet it is difficult to predict the ratio of aldehydes produced. Since these aldehydes are markers of biological activity, quantitative prediction of product ratios is desirable. Density functional calculations are used to study the thermodynamic and kinetic aspects of the first three steps in the mechanism of lipid peroxidation of arachidonic acid. It is found that the relative stability of peroxyl radical intermediates resulting from hydrogen abstraction and subsequent oxidation correlates with localization of the valence molecular orbitals on the peroxyl group. In addition, simple diene models are used to show that the most stable isomers of the peroxyl radicals are trans, trans, where the peroxyl group is located away from the bis-allylic carbon. Finally, the most stable peroxyl radicals originating from arachidonic acid are identified: these arise from hydrogen abstraction at the C13 position and exhibit trans, trans stereochemistry around the site of peroxidation.