Evaluation of newly synthesized 2-(thiophen-2-yl)-1H-indole derivatives as anticancer agents against HCT-116 cell proliferation via cell cycle arrest and down regulation of miR-25.

In the present study, we prepared new sixteen different derivatives. The first series were prepared (methylene)bis(2-(thiophen-2-yl)-1H-indole) derivatives which have (indole and thiophene rings) by excellent yield from the reaction (2 mmol) 2-(thiophen-2-yl)-1H-indole and (1 mmol) from aldehyde. The second series were synthesized (2-(thiophen-2-yl)-1H-indol-3-yl) methyl) aniline derivatives at a relatively low yield from multicomponent reaction of three components 2-(thiophen-2-yl)-1H-indole, N-methylaniline and desired aldehydes. The anticancer effect of the newly synthesized derivatives was determined against different cancers, colon, lung, breast and skin. The counter screening was done against normal Epithelial cells (RPE-1). The effect on cell cycle and mechanisms underlying of the antitumor effect were also studied. All new compounds were initially tested at a single dose of 100 µg/ml against this panel of 5 human tumor cell lines indicated that the compounds under investigation exhibit selective cytotoxicity against HCT-116 cell line and compounds (4g, 4a, 4c) showed potent anticancer activity against HCT-116 cell line with the inhibitory concentration IC50 values were, 7.1±0.07, 10.5± 0.07 and 11.9± 0.05 µΜ/ml respectively. Also, the active derivatives caused cell cycle arrest at the S and G2/M phase with significant(p < 0.0001) increase in the expression levels of tumor suppressors miR-30C, and miR-107 and a tremendous decrease in oncogenic miR-25, IL-6 and C-Myc levels. It is to conclude that the anticancer activity could be through direct interaction with tumor cell DNA like S-phase-dependent chemotherapy drugs. Which can interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil and which were highly effective in killing the cancer cells. This data ensures the efficiency of the 3 analogues on inducing cell cycle arrest and preventing cancer cell growth. The altered expressions explained the molecular mechanisms through which the newly synthesized analogues exert their anticancer action.

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents.

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series of sulfonamide derivatives based on the pyrazole or pyridine moieties 3a, b, 7-9, 11-13, 15a, b, and 16 were synthesized from amine compounds with sulfonyl chloride derivatives. The structures of sulfonamide derivatives were elucidated via spectroscopy (1H and 13C NMR). The sulfonamide derivatives were biologically assessed in vitro for their anti-diabetic (α-amylase and α-glucosidase inhibition) and anti-Alzheimer's (acetylcholinesterase inhibition) activities. The biological results revealed that compound 15a is a powerful enzyme inhibitor for α-amylase and α-glucosidase. Also, compound 15b demonstrated inhibitor activity against the acetylcholinesterase enzyme. The structure-activity relationship study of sulfonamide derivatives was accomplished. Furthermore, complementary in silico molecular properties, drug-likeness, ADMET prediction, and surface properties of the two more powerful derivatives 15a and 15b were fulfilled and computed. These studies recommend 15a and 15b as candidates with modifications in their structures before the in vivo assays.

Design, synthesis, in vitro anticancer, molecular docking and SAR studies of new series of pyrrolo[2,3-d]pyrimidine derivatives.

The current study involves the design and synthesis of a newly synthesized pyrrolo[2,3-d]pyrimidine derivatives to contain chlorine atoms in positions 4 and 6 and trichloromethyl group in position 2 using microwave technique as a new and robust approach for preparation of this type of pyrrolo[2,3-d]pyrimidine derivatives. The chemical structure of the synthesized pyrrolo[2,3-d]pyrimidine derivatives 3-19 was well-characterized using spectral and elemental analyses as well as single-crystal X-ray diffraction. All compounds were tested in vitro against seven selected human cancer cell lines, namely, MCF7, A549, HCT116, PC3, HePG2, PACA2 and BJ1 using MTT assay. It was found that compounds 14a, 16b and 18b were the most active toward MCF7 with IC50 (1.7, 5.7, and 3.4 µg/ml, respectively) relative to doxorubicin (Dox.) (26.1 µg/ml). Additionally, compound 17 exerted promising cytotoxic effects against HePG2 and PACA2 with IC50 (8.7 and 6.4 µg/ml, respectively) relative to Dox. (21.6 and 28.3 µg/ml, respectively). The molecular docking study confirmed our ELISA result which showed the promising binding affinities of compounds 14a and 17 against Bcl2 anti-apoptotic protein. At the gene expression level, P53, BAX, DR4 and DR5 were up-regulated, while Bcl2, Il-8, and CDK4 were down-regulated in 14a, 14b and 18b treated MCF7 cells. At the protein level, compound 14b increased the activity of Caspase 8 and BAX (18.263 and 14.25 pg/ml) relative to Dox. (3.99 and 4.92 pg/ml, respectively), while the activity of Bcl2 was greatly decreased in 14a treated MCF7 (2.4 pg/ml) compared with Dox. (14.37 pg/ml). Compounds 14a and 14b caused cell cycle arrest at the G1/S phase in MCF7. Compounds 16b and 18b induced the apoptotic death of MCF7 cells. In addition, the percentage of fragmented DNA was increased significantly in 14a treated MCF7 cells.

Synthesis of a New Chelating Iminophosphorane Derivative (Phosphazene) for U(VI) Recovery.

A new synthetic chelating N-hydroxy-N-trioctyl iminophosphorane (HTIP) was prepared through the reaction of trioctylphosphine oxide (TOPO) with N-hydroxylamine hydrochloride in the presence of a Lewis acid (AlCl3). Specifications for the HTIP chelating ligand were successfully determined using many analytical techniques, 13C-NMR, 1H-NMR, FTIR, EDX, and GC-MS analyses, which assured a reasonable synthesis of the HTIP ligand. The ability of HTIP to retain U(VI) ions was investigated. The optimum experimental factors, pH value, experimental time, initial U(VI) ion concentration, HTIP dosage, ambient temperature, and eluents, were attained with solvent extraction techniques. The utmost retention capacity of HTIP/CHCl3 was 247.5 mg/g; it was achieved at pH = 3.0, 25 °C, with 30 min of shaking and 0.99 × 10-3 mol/L. From the stoichiometric calculations, approximately 1.5 hydrogen atoms are released during the extraction at pH 3.0, and 4.0 moles of HTIP ligand were responsible for chelation of one mole of uranyl ions. According to kinetic studies, the pseudo-first order model accurately predicted the kinetics of U(VI) extraction by HTIP ligand with a retention power of 245.47 mg/g. The thermodynamic parameters ΔS°, ΔH°, and ΔG° were also calculated; the extraction process was predicted as an exothermic, spontaneous, and advantageous extraction at low temperatures. As the temperature increased, the value of ∆G° increased. The elution of uranium ions from the loaded HTIP/CHCl3 was achieved using 2.0 mol of H2SO4 with a 99.0% efficiency rate. Finally, the extended variables were used to obtain a uranium concentrate (Na2U2O7, Y.C) with a uranium grade of 69.93% and purity of 93.24%.