Synthesis and Evaluation of 198Au/PAMAM-MPEG-FA against Cancer Cells.

BACKGROUND: There is a significant dearth of clinical biochemistry researches to evaluate the facility of exploitation of folate targeted radioactive gold-labeled anti-cancer drugs against various cancer cell lines. OBJECTIVE: The aim of this paper was to develop a gold-based compound with an efficient therapeutic potential against breast cancer. To this end, the synthesis of the 198Au/PAMAM-MPEG-FA composite was considered here. METHODS: The radioactive gold (198Au) nanoparticles were encapsulated into Folic acid (FA)-targeted Polyamidoamine dendrimer (PAMAM) modified with Maleimide-Polyethylene glycol Succinimidyl Carboxymethyl ester (MPEG). After that, anticancer assessments of the prepared 198Au/PAMAM-MPEG-FA hybrid mater against breast cancer were investigated. Further studies were also devised to compare the anticancer capabilities of the 198Au/PAMAM-MPEG-FA composite with the synthesized P-MPEG, 197Au/P-MPEG, 197Au/P-MPEG-FA, 197Au/P-FA and 198Au/P-MPEG-FA conjugates. The prepared drugs were characterized by means of various analytical techniques. The radionuclidic purity of the 198Au/P-MPEG-FA solution was determined using High Purity Germanium (HPGe) spectroscopy and its stability in the presence of human serum was studied. The cell uptake and toxicity of the prepared drugs were evaluated in vitro, and some comparative studies of the toxicity of the drugs were conducted towards the MCF7 (Human breast cancer cell), 4T1 (Mice breast adenocarcinoma cell) and C2C12 (Mice muscle normal cell). RESULTS: The results showed that cell uptake of 198Au/P-MPEG-FA nanoparticles is high in the 4T1 cell line and the order of uptake is as 4T1> MCF7> C2C12. Moreover, of the tested compounds, 198Au/P-MPEG-FA had the highest toxicity towards the cancerous 4T1 and MCF7 in all concentrations after 24, 48 and 72h (P < 0.001). Furthermore, the cytotoxicity of the drugs was concentration-dependent. CONCLUSION: On the basis of the present research, 198Au/P-MPEG-FA has been proposed as a good candidate for the induction of cell death in breast cancer, although further experimental and clinical investigations are required.

5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer's disease modifying agents.

In this study, new derivatives of 5,6-diphenyl triazine-thio methyl triazole hybrid were designed, synthesized and evaluated as multifunctional agents for Alzheimer's disease. Among all synthesized compounds, 4a and 4h showed the best inhibitory activities against BACE1 (40% and 37.5% µM inhibition at 50 µM, respectively). Molecular docking studies showed that compound 4a occupied the entire BACE1 enzyme and the thio triazine fragment deeply penetrates into S2 binding site via two hydrogen bonds with Thr72 and Gln73 amino acids. Different aromatic moieties occupy S'2 pocket via hydrophobic interactions. 6-Phenyl ring also had a potential hydrophobic interaction with S1 pocket. In vitro ChE inhibitory assay demonstrated that most of the derivatives exhibited more selectivity toward BuChE than AChE. 4c as the most potent BuChE inhibitor displayed an IC50 value of 6.4 µM, and 4b exhibited AChE inhibitory activity with 25.1% inhibition at 50 µM. Further, molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket. Moreover, molecular docking study of 4a, 4b and 4c with ChE active site was also performed.

Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation.

Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO2 groups at the para position of the phenyl ring, namely compounds 7c (IC50 = 8.55 ±â€¯3.37 µM) and 7d (IC50 = 11.42 ±â€¯2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid ß peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC50 = 44.42 ±â€¯7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.

Chemical constituents of the essential oil from aerial parts and fruit of Anisosciadium orientale.

The essential oils from aerial parts and fruits of Anisosciadium orientale DC. growing wild in Iran were obtained by hydrodistillation and analyzed by GC and GC/MS. Seventy-one compounds were identified in the fruit oil and fifteen in the oil from the aerial parts. The main oil components of the fruits and aerial parts were myristicin (33.5%-33.7%), alpha-terpinolene (22%-25.8%) and limonene (19.5%-19.7%). Some compounds, such as geranyl butyrate and germacrene-D, were only detected in the fruit oil.

Isolation and characterization of a novel gamma-radiation-resistant bacterium from hot spring in Iran.

30 pure colonies with various colors and shapes were isolated from the samples of water and mud which were collected from the Abe-Siah hot springs in Ramsar, a city in north of Iran, with high-level of radiation (up to 4 Gy). Colonies were irradiated by 22 KGy radiations and only one of them survived. The survived bacterium with an optimum growth of 30 to 37 degrees C, pH 6 to 7, and at minimum of 5% NaCl concentration showed promising characteristics. This strain is aerobic, mesophilic, white colony, with catalase-positive, oxidase-negative, non motile, spore forming, rod-shape and finally Gram positive. Strain Bacillus sp. WHO represented a strain of genus Bacillus megaterium according to a phylogenetic analysis of the 16S rDNA and biochemical features. Its radio-resistancy was compared with E. coli and B. megaterium which were inactivated in 2 KGy and 5.9 KGy respectively. In order to reveal the mechanisms of this extreme radio-resistancy and WHO DNA repair system we examined its proteomic map, following gamma-irradiation, using two-dimensional polyacrylamide gel electrophoresis and silver-staining. The expression levels of majority number of protein spots showed significant changes under radiation stress.