Medicinal Chemistry - Volume 8, Issue 6, 2012

Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. FoxG1 is a transcriptional repressor, whose function has been elucidated recently. FoxG1 overexpression was found to be associated with medulloblastoma and hepatoblastoma. It was suggested that the inhibition of FoxG1 could be a potential target for the development of molecular therapeutics in such type of cancers. Since, experimentally derived structure for FoxG1 is unavailable in any of the structural databases, modeling of the DNA binding domain of this protein was carried out. Potential binding sites on the protein surface were predicted. Pharmacophoric features were derived from the binding site that lies near the protein-DNA binding interface and this pharmacophore was employed for virtual screening of compounds. To the best of our knowledge, this is the first pharmacophore model proposed for screening inhibitors of FoxG1, which may interfere with its transcriptional repressor functionality. The interactions of the binding site residues with the top scoring ligand hits were analyzed. These ligands may be used for the development of potential inhibitors of FoxG1 protein.

The main use of glycopeptide antibiotics is treatment of infections which are resistant to the commonly used β- lactam antibiotics. Antitumor activity has also been reported for some glycopeptide antibiotics like bleomycin. In the present study we investigated the chemotherapeutic and diagnostic potential of two imaging agent derivatives of the glycopeptide antibiotic vancomycin. For the first conjugate, vancomycin was coupled to the fluorescent dye rhodamine, used in confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS). The second conjugate consisted of vancomycin coupled to gadolinium-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (GdDOTA), a magnetic resonance imaging (MRI) contrast agent. The cellular uptake, specificity, and the accessibility by imaging methods of the two vancomycin conjugates was evaluated on 8 human cell lines (one benign, 7 malignant) by CLSM, FACS, and MRI experiments. Cytotoxicity of both vancomycin conjugates was determined in the FACS experiments with the annexin test indicating disrupted cell membranes. Some of the malignant cell lines showed clearly stronger uptake than the others and the benign cell line was among the cell lines with the lowest uptake. In the annexin test the cytotoxicity could be correlated to the conjugate uptake for all cell lines. The intracellular uptake of the vancomycin conjugates and the increased uptake into some of the malignant cell lines were interesting findings which should be further pursued.

256 pediatric patients with primary hyperlipidemia aged 14.2 ± 8.5 years (females: 155; males:101) seen in our lipid clinic were evaluated retrospectively to assess the effect of multiple lipid-lowering treatment (diet only, diet+glucomannan 1.000 mg/day (G), diet+ezetimibe (E) 10 mg/day and diet+atorvastatin (A) 10 mg/day). The patients were assigned to four groups according to their type of treatment: A-Diet (#82; age 12.7 ± 8 years; females 52, males:30); B-Diet+G (#78; age 13.3 ± 9 years; females 61, males 17); C-Diet+E 10 mg/day (#50; age 14.5 ± 7 years; females 31, males 19); D-Diet+A 10 mg/day (#46; age 16.4 ± 10 years; males 35, females 11). The follow-up visits were at 3, 6 and 9 months, respectively. The time period considered was of 9 months. The results obtained in the four groups after 9 months of treatment are given below: Group A: Total Cholesterol (TC) (-20%), LDL-Cholesterol (LDLC) (-26%), triglycerides (TG) (-25%), nonHDLCholesterol (nonHDLC) (-26%) levels, and TC/HDLC ratio (-21%) were statistically significant reduced (all: P<0001). HDLC was not significantly increased (+2%). The body weight (BW) mean change in the group was statistically significant (-22%; P≤0.001). Group B: TC (-24%), LDLC (-32%), TG (-29%), nonHDLC (-32%) levels and TC/HDLC (-26%) were significantly decreased (all: P≤0.001). HDLC showed a -2.3% not significant decrease. The BW mean change was not statistically significant (-18%). Group C: TC (-36%), LDLC (-51%), nonHDLC (-45%) levels and TC/HDLC (-38%) were significantly decreased (all: P≤0.001). HDLC (+4%) was only slightly increased, and TG (-16%) decreased, but the changes were not statistically significant. The BW mean change was not statistically significant (-15%). Group D: TC (-47%), LDLC (-63%), TG (-23%) and nonHDLC (-58%) levels and TC/HDLC (-50%) showed a statistically significant reduction (all: P≤0001). HDLC concentration in plasma showed only a slight not significant reduction (- 4%). The BW mean change was statistically significant (-20%; P≤0.001). Hyperlipidemia in children can be successfully treated without side effects. The most severe hyperlipidemia is, the most appropriate treatment (diet only,or diet+G, or diet+drugs) is to be given. The reduction of TC/HDLC ratio in childhood prevents future increase of cardiovascular risk in adulthood.

We proposed a method of synthesis to produce [11C]Choline using TRACERlab FXc module that utilized gas phase iodination. The product had radiochemical purity of 99.79 + 0.14 % and specific activity of 45.7 + 7.59 GBq/µmol. [11C]Choline did not have at the moment a specific monograph in European Pharmacopeia therefore we used, when possible, as quality controls reference the monograph of [18F]FDG and we proposed suitable methods to verify radiochemical purity and to quantify residual DMAE and choline amounts.

Two series of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles (4a-l and 5a-l) were synthesized by cyclodehydration of adamantan-1-carboxylic acid/adamantylacetic acid with various aryl hydrazides (3a-l) in the presence of POCl3. The synthesis was supported by spectroanalytical techniques and verified further by crystal structure determination of compounds 4e and 5k. The synthesized compounds were screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. Compound 5b exhibited a moderate activity in vitro for the replication of both virus types, suggesting for further structural modification as a new lead in the development of an antiviral agent.