Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents

Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec). We evaluated their inhibitory activities against pan HDAC and HDAC1 isoform. Four compounds (8f, 8q, 8r and 8u) showed significant cytotoxicity with IC50 in the range of 0.53–57.59 μM on cancer cells and potent pan-HDAC inhibitory activity (consists of HDAC isoenzymes) (IC50 = 0.80–14.81 μM) and HDAC1 inhibitory activity (IC50 = 0.47–0.87 μM and also, had no effect on Huvec (human normal cell line) viability (IC50 > 100 μM). Among them, 8u displayed a higher potency for HDAC1 inhibition with IC50 value of 0.47 ± 0.02 μM near equal to the reference drug Entinostat (IC50 = 0.41 ± 0.06 μM). Molecular docking studies and Molecular dynamics simulation of compound 8a displayed possible mode of interaction between this compound and HDAC1enzym

Characterization of Encapsulated Berberine in Yeast Cells of Saccharomyces Cerevisiae

Abstract Berberine was loaded in yeast cells of Saccharomyces cerevisiae as a novel pharmaceutical carrier to improve the treatment of many diseases. The yeast-encapsulated active materials showed high stability and bioavailability due to the enhanced solubility and sustained releasing. In this study, different characteristics of prepared berberine loaded yeast cells (loading capacity, release kinetic order, MIC and stability) were evaluated by different analytical methods (fluorescence spectroscopy, HPLC and SEM).The loading capacity was about 78% ± 0.6%. Berberine release patterns of microcapsules happened in two different stages and followed by zero and first-order kinetic,respectively. About 99% of all active material released during 34 hours. MIC was improved by berberine loaded microcapsules in comparison with berberine powder. The microcapsules were completely stable. Berberine loaded Sac. cerevisiae could be considered as a favorite sustained release drug delivery system. The yeast would be applied as an efficient carrier to improve various properties of different active materials

Nicotine Content of Domestic Cigarettes, Imported Cigarettes and Pipe Tobacco in Iran

Background: There are many different kinds of cigarettes and tobacco available in the market. Since nicotine content of various brands of cigarettes are very variable, therefore evaluation and comparison of nicotine content of different brands of cigarettes is important. The goal of the present study was to determine and compare nicotine content of various domestic and imported cigarettes available in the area. Methods: Fourteen popular imported brands and nine popular domestic brands of cigarettes and three available brands of tobaccos were investigated for the amounts of nicotine content. Nicotine was extracted from each cigarette and tobacco samples and was analyzed by high performance liquid chromatography (HPLC) method. Findings: The amount of nicotine in each cigarette was from 6.17 to 12.65 mg (1.23 ± 0.15 percent of tobacco weight in each cigarette) in domestic cigarettes. It was between 7.17-28.86 mg (1.80 ± 0.25 percent of tobacco weight in each cigarette) for imported cigarette, and between 30.08- 50.89 mg (3.82 ± 1.11 percent) for the pipe nicotine. There was significant difference in nicotine amount between imported and domestic brands of cigarettes. There was also no significant difference in nicotine content between light and normal cigarettes in imported brands. Conclusion: Nicotine content of all tested cigarettes, imported and domestic brands, were higher than the international standard.   Keywords: Nicotine, Tobacco, Cigarettes, Human health, Bran

Anti-Proliferative Potential of Fluorinated Curcumin Analogues: Experimental and Computational Analysis and Review of the Literature

BACKGROUND: Curcuminoids, flavoring, and coloring agents in food have potent antioxidant, anti-tumor activity, and anti-inflammatory effects. However, they are rapidly metabolized to lesser active metabolites. Therefore, various studies have been conducted to synthesize new and stable curcumin analogues with enhanced therapeutic activity. METHODS: Fluorinated curcumin compounds (2a-2f) were synthesized by Knoevenagel condensation between fluorobenzaldehydes (1a-1f) with curcumin. Fluorinated demethoxycurcumin (3a) was synthesized by condensation between demethoxycurcumin and 3,4-difluorobenzaldehyde (1f). The structures of these compounds were confirmed by FTIR, 1H-NMR, 13C-NMR, 19FNMR, and mass spectroscopy. Antiproliferative activities of these synthetic compounds were evaluated against breast cancer cells (4T1), melanoma cancer cells (B16F10), and normal cell lines (NIH 3T3) using MTT assay. The interaction of curcumin, 2f and 3a with several proteins (1HCL, 2ZOQ, 3D94, 5EW3, 4WA9, 1XKK, 6CCY) was investigated. The structural preservation of the epidermal growth factor receptor (EGFR) was investigated by molecular dynamics simulation. RESULTS: The spectroscopic data obtained confirmed the proposed structure of fluorinated analogues. The results showed that compounds 2f and 3a inhibited cancer cells proliferation significantly more than other compounds. Compounds 2f and 3a showed the highest affinity and lowest binding energy with EGFR. The binding energies were -7.8, -10, and - 9.8 kcal/mol for curcumin, 2f and 3a with EGFR, respectively. The molecular docking results demonstrated that compounds 2f and 3a were firmly bound in a complex with EGFR via the formation of a hydrogen bond. CONCLUSION: In summary, we found that fluorinated demethoxycurcumin and fluorinated curcumin induces cancer cell death and binds to EGFR with high affinity