Antitumor activities of a novel fluorinated small molecule (A1) in CT26 colorectal cancer cells: molecular docking and in vitro studies.

Chemotherapeutic treatment of colorectal cancer (CRC) has not been satisfactory until now; therefore, the discovery of more efficient medications is of great significance. Based on available knowledge, the CXCL12/CXCR4 axis plays a significant role in tumorigenesis, and inhibition of CXCR4 chemokine receptor with AMD3100 is one of the most known therapeutic modalities in cancer therapy. Herein, N, N''-thiocarbonylbis(N'-(3,4-dimethylphenyl)-2,2,2-trifluoroacetimidamide) (A1) was synthesized as a potent CXCR4 inhibitor. A1 inhibitory activity was first evaluated employing Molecular Docking simulations in comparison with the most potent CXCR4 inhibitors. Then, the antiproliferative and cytotoxic effect of A1 on CT26 mouse CRC cells was investigated by MTT assay technique and compared with those of the control molecule, AMD3100. The impact of the target compounds IC50 on apoptosis, cell cycle arrest, and CXCR4 expression was determined by flow cytometry technique. Our finding demonstrated that A1 induces a cytotoxic effect on CT26 cells at 60 µg/mL concentration within 72 h and provokes cell apoptosis and G2/M cell cycle arrest in comparison with the untreated cells, while AMD3100 did not show a cytotoxic effect up to 800 µg/mL dose. The obtained results show that A1 (at a concentration of 40 µg/mL) significantly reduced the proliferation of CT26 cells treated with 100 ng/mL of CXCL12 in 72 h. Moreover, treatment with 60 µg/mL of A1 and 100 ng/mL of CXCL12 for 72 h significantly decreased the number of cells expressing the CXCR4 receptor compared to the control group treated with CXCL12. Eventually, the obtained results indicate that A1, as a dual-function fluorinated small molecule, may benefit CRC treatment through inhibition of CXCR4 and exert a cytotoxic effect on tumor cells.Communicated by Ramaswamy H. Sarma.

Survey reaction of 2-amino-N-(aryl) benzimidamides with ninhydrin in different conditions and investigation of reaction mechanism using density functional theory (DFT).

In this investigation, firstly, 1-(2-amino-phenyl)-N-(aryl) methane diamine derivatives were synthesized by reaction of 2-aminobenzo nitrile with aromatic amines in the presence of aluminum chloride as the catalyst. Then, the reaction of these intermediates with ninhydrin in different conditions was investigated. The reaction between ninhydrin and 2-amino-N'-(aryl) benzimidamide derivatives in water as solvent under reflux conditions resulted in the synthesis of diazepine derivatives. The same results were obtained when the reaction was done in EtOH and in the presence of a few drops of sulfuric acid at room temperature. Also, this reaction was carried out in ethanol as solvent without the presence of sulfuric acid at room temperature which resulted in the synthesis of spiro [indene-2,2'-quinazoline] derivatives. And finally, the reaction was carried out in ethanol as solvent without the presence of sulfuric acid at the reflux conditions which resulted in the synthesis of isoquinolino-quinazoline derivatives. These N-heterocycles compounds are important biologically. Mild reaction conditions, simple procedure and purification and also product diversity with changing conditions are important advantages of this method. Also, to better understanding reaction mechanism on the condensation reactions of 2-amino-N-(aryl) benzimidamides with ninhydrin in different conditions, density functional theory (DFT)-based quantum chemical methods have been applied. Calculated atomic charges suggest that the C-1 (+ 0.54 a.u.) center of ninhydrin is a better electrophile than C-2 (+ 0.42 a.u.) center.

Friedel-Crafts synthesis of bis(trifluoromethylated)-4-aryl-3,4-dihydroquinazolines, bis(trifluoromethylated)-3,4-dihydroquinazoline-4-ols and trifluoromethyl arylketoimines using N-aryltrifluoroacetimidoyl chlorides and benzene derivatives.

A simple and straightforward approach to access biologically important N-heterocycles, namely bis(trifluoromethylated)-4-aryl-3,4-dihydroquinazolines, bis(trifluoromethylated)-3,4-dihydroquinazoline-4-ols and trifluoromethyl arylketoimines, as a group of important frameworks or initial substance from N-aryltrifluoroacetimidoyl chlorides with benzene derivatives via Friedel-Crafts reaction has been described. This novel strategy provides synthesis of trifluoromethylated dihydroquinazolines and trifluoromethyl arylketoimines in good to excellent yields.

Resistance pattern of Escherichia coli to levofloxacin in Iran: a narrative review.

Fluoroquinolones (FQs) are widely used in the treatment of infections caused by Escherichia coli. FQs are broad spectrum antibiotics with high tissue penetration, and ease of use. Therefore, given the concerns existing about drug resistance, we aim to review the latest findings about resistance patterns to levofloxacin (LVX) along with other FQs in E. coli infections in different parts of Iran. Evidence shows that quinolones have been used in Iran for nearly 50 years, and that 0-65% of E. coli isolates show resistance to FQs. In the western parts of Iran, the highest rate of resistance to LVX (66.7%) has been reported among patients having urinary tract infections with E. coli isolates. Few studies and information exist on the antimicrobial resistance of E. coli to LVX in different geographical locations of Iran. However, the findings of various studies on this subject show that E. coli resistance to LVX is more in the western part of Iran than in central and southern regions, but it is similar among inpatients and outpatients. Therefore, it is reasonable advisable to limit the overuse, inappropriate prescription, and self-medication of LVX to prevent the induction of FQ-resistant strains. Accordingly, in order to obtain a clearer image of resistance to FQs, especially LVX in E. coli in Iran, more extensive investigations in different geographical locations and periods of time are required. In addition, antimicrobial stewardship would be helpful in this regard.

Intramolecular oxidative cyclization of N-(2,2,2-trifluoro-1-(phenylimino)ethyl)benzimidamide.

A fast and convenient method for synthesis of 1,3-diaryl-5-(trifluoromethyl)-1H-1,2,4-triazole compounds has been described via intramolecular oxidative cyclization of the N-(2,2,2-trifluoro-1-(arylimino)ethyl)benzimidamide intermediates by I2/KI in excellent yields without any purification. N-(2,2,2-Trifluoro-1-(arylimino)ethyl)benzimidamide intermediates which are used in this project have been synthesized from the reaction of N-aryl-2,2,2-trifluoroacetimidoyl chlorides and benzamide hydrochloride derivatives at room temperature for the first time.

Iodine/potassium iodide catalyst for the synthesis of trifluoromethylated quinazolines via intramolecular cyclization of 2,2,2-trifluoro-N-benzyl-N'-arylacetimidamides.

An efficient and simple protocol for the synthesis of trifluoromethylated quinazolines has been described by I2-/KI-promoted oxidative C(sp3)-C(sp2) bond under the optimal oxidative cyclization reaction conditions. The required 2,2,2-trifluoro-N-benzyl-N'-arylacetimidamides are readily prepared from the corresponding acetimidoyl chlorides and benzylamines under a nucleophilic substitution reaction in the form of in situ. The merits of this protocol are the use of inexpensive molecular iodine, metal-free oxidative coupling and good to excellent yields.

Indole itself and its novel derivative affect PML cells proliferation via controlling the expression of cell cycle genes.

Recently the role of indole and pyran rings in carcinogenesis has been well studied. Here we studied the effects and the possible mechanisms of the action of basal indole (I3A) and its novel indole derivative (C19H15F3N2O) on inhibition of proliferation cells in acute promyelocytic leukemia NB4 cell line by examining the expression of cell cycle genes. We treated NB4 cells with concentration of C19H15F3N2O for 24-72 h. The MTT and PI/Annexin V examinations were employed for assessment of the proliferation and apoptosis of NB4 cells. Both of Cyclin D and P21 were detected by the Real-time PCR. The western blotting analysis was also performed to show the protein levels for P21. A difference was regarded significant if p-value was less than 0.05. MTT assay showed that 15.12-1000 µg/mL C19H15F3N2O caused a time and concentration-dependent inhibition of NB4 cell proliferation. Exposure to higher concentrations of C19H15F3N2O resulted in significantly increased apoptosis rate in NB4 cells. RT PCR showed that C19H15F3N2O has up-regulated the expression of P21 and down-regulated the expression of Cyclin D. Western blotting experiments also demonstrated that the P21 expression in C19H15F3N2O treated cells has significantly increased, where compared with either untreated control cells or I3A treated cells. This newly (C19H15F3N2O) was able to inhibit NB4 cells proliferation and causes apoptosis of these cells more than I3A, and these effects are probably facilitated via cell cycle arrest. C19H15F3N2O might probably be introduced as a promising organic therapeutic reagent against APL.

Preparation and optimization photocatalytic activity of polymer-grafted Ag@AgO core-shell quantum dots.

A linear-dendric copolymer containing polyethylene glycol-polycitric acid used as a capping agent to the green inter-matrix synthesis of silver/silver oxide core-shell quantum dots (Ag@AgO QDs). Water-soluble Ag@AgO QDs were synthesized with high yield and narrow size distribution. Here, Ag ions were trapped in the polymer branches and covalently bonded to it. Another sample of Ag@AgO QDs was synthesized through the same method and conditions without any capping agent (raw nanoparticles). Structure, size distribution, and morphology of raw and copolymer-grafted nanoparticles were identified using X-Ray diffraction, field emission scanning electron microscopy (FESEM), and high-resolution transmission electron microscopy (HRTEM). The results from XRD pattern and UV spectra confirmed the Ag@AgO structure of both nanoparticles. From the FESEM image, the size of Ag nanoparticles obtained at the range of 1-20 nm. HRTEM image of grafted nanoparticles directly showed that these nanoparticles have very tiny size in the range of 1-2 nm and presented in the form of core-shell Ag@AgO. Thus, both raw and polymer-grafted samples are in the range of quantum dots (QDs). Raw and polymer-grafted Ag@AgO QDs which take the advantage of water solubility and biosafety, were used as photocatalyst for degradation of cationic methylene blue (MB) and anionic methyl orange (MO) dyes at low and high concentrations of each dye. Results shows using polymer-grafted QDs leads to a significant enhancement both in the efficiency and rate of dye degradation, compared to the case of using raw nanoparticles.

Expedient approach to synthesis of 4-hydroxy-2-(trifluoromethyl) quinolines through an intramolecular cyclization of ethyl 2-cyano-4,4,4-trifluoro-3 (arylamino)but-2-enoate derivatives.

Ethyl 2-cyano-4,4,4-trifluoro-3-(phenylamino)but-2-enoates have been synthesized by reaction of ethyl 2-cyanoacetate with trifluoroacetimidoyl chloride derivatives using sodium hydride in acetonitrile by conventional and microwave irradiation methods. Then, intramolecular cyclization of these products in nitrobenzene under reflux conditions afforded a new series of substituted (trifluoromethyl)quinoline-3-carbonitrile derivatives in quantitative yields.

Evaluating of OCT-4 and NANOG was differentially regulated by a new derivative indole in leukemia cell line.

BACKGROUND: The potential exists to improve treatment through characterization of tumor stem cells and identification of therapeutic targets Using OCT-4 and NANOG genes. Here we have synthesized and investigated the potential of; New Indole-3-carbaldehyde derivative (NI-3-CD) in inhibiting the expression of self-renewal regulatory factors and cancer stem cell gene in a leukemia cell line NB4. METHODOLOGY: The NB4 cells were cultured in RPMI1640 medium contained NI-3-CD and I3F (15.12-1000µg/mL) for 24, 48 and 72h. Inhibition of cell proliferation was assessed by trypan blue staining technique and MTT assay. The percentage of apoptotic cells was determined by flow cytometry analysis using Annexin V/PI apoptosis detection kit. The fold changes of NANOG/OCT4 expression against ß-actin were determined by real-time-PCR technique. Western blotting analysis was also applied for evaluating the expression of NANOG/OCT4 at protein level. Data were analyzed by student t and repeated measure tests. Differences were considered significant if (P<0.01). RESULTS: There was a significant difference in cell viability, when various concentrations of NI-3- were used for 24, 48 and 72h in comparison to I3C regarding the cellular viability. Furthermore, the NI-3-CD, had markedly elevated anticancer activity than I3C (IC50 values for novel I3C in 24, 48 and 72h were 225.77, 123.13 and 63.72M respectively while for I3C were 728.05, 407.82 and 277.92M respectively). Flow cytometry results exhibited an obviously significant augmentation in apoptotic NB4 cells. Real Time- PCR analysis indicated that the expression of NANOG/OCT4 was down regulated in compare to untreated control cells and I3C treated cells (P<0.05). In concert with RT-PCR, western blot analysis showed that the OCT4 expression in NI-3-CD treated cells was also significantly decreased in compare to both untreated control cells and I3C treated cellular populations. CONCLUSION: Our results imply that NI-3-CD treatment decreases the sphere-forming ability of NB4 cells. In summary, this study provides valuable information on the presence of stem-cell genes expression in NB4 cells.

The novel Indole-3-formaldehyde (2-AITFEI-3-F) is involved in processes of apoptosis induction?

AIM AND OBJECTIVES: Balancing between Bax and Bcl-2 plays critical roles in both proliferation and self-renewal activation of cancer cells. Indole-3-formaldehyde derivatives limit the growth and facilitate cell death in different cell systems. In this study, we introduced a novel indole derivative (2-AITFEI-3-F) with tendency to facilitate apoptosis in NB4 line in comparison to basal Indole-3-formaldehyde (I3F). METHODS: The NB4 cells were cultured in RPMI1640 medium contained 2-AITFEI-3-F and I3F (15.12-1000µg/mL) for 24, 48 and 72h. Inhibition of cell proliferation was assessed by trypan blue staining technique and MTT assay. The fold changes of Bax/Bcl-2 expression against ß-actin were determined by real-time-PCR technique. Western blotting analysis was also applied for evaluating the expression of Bax and Bcl2 at protein level. Data were analyzed by student t and repeated measure tests. Differences were considered significant if (P<0.01). RESULTS: There was a significant difference in cell viability, when various concentrations of 2-AITFEI-3-F (but similar to I3F) were used for 24, 48 and 72h in comparison to I3F regarding the cellular viability (P<0.05). Real time PCR and Western blotting analysis indicated that the gene and protein expression level of Bcl-2 down-regulated while Bax was up-regulated in compare to untreated control cells and cells treated with I3F (P<0.01). CONCLUSION: According to these findings, the novel indole derivative 2-AITFEI-3-F probably triggered apoptosis of NB4 cells by modulating Bax/Bcl-2 ratio. Furthermore, the 2-AITFEI-3-F had markedly displayed anti-cancer activity than I3F.

One-pot synthesis of novel (2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl) pyrrolidine-2-carboxamides via TiO2-NPs and Pd(PPh3)2Cl2 catalysts and investigation of their biological activities.

A new class of (2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide compounds was synthesized by a facile one-pot reaction of trans-4-hydroxy proline and trifluoroacetimidoyl chlorides in the presence of [Formula: see text]-nanoparticles as a catalyst and sodium bicarbonate as a base. Synthesized compounds showed cytotoxicity with [Formula: see text] values of 15.3-70.3 [Formula: see text] against K562 (Homo sapiens, human) cells. The results of the study provide a valuable method for one-pot synthesis of trans-4-hydroxy proline-based N-(2,2,2-trifluoroacetylated) compounds. Also, these compounds show significant pharmaceutical activities as antibacterial and antifungal reagents.

Simultaneous spectrophotometric determination of copper, cobalt, nickel and iron in foodstuffs and vegetables with a new bis thiosemicarbazone ligand using chemometric approaches.

A newly synthesized bis thiosemicarbazone ligand, (2Z,2'Z)-2,2'-((4S,5R)-4,5,6-trihydroxyhexane-1,2-diylidene)bis(N-phenylhydrazinecarbothioamide), was used to make a complex with Cu(2+), Ni(2+), Co(2+) and Fe(3+) for their simultaneous spectrophotometric determination using chemometric methods. By Job's method, the ratio of metal to ligand in Ni(2+) was found to be 1:2, whereas it was 1:4 for the others. The effect of pH on the sensitivity and selectivity of the formed complexes was studied according to the net analyte signal (NAS). Under optimum conditions, the calibration graphs were linear in the ranges of 0.10-3.83, 0.20-3.83, 0.23-5.23 and 0.32-8.12 mg L(-1) with the detection limits of 2, 3, 4 and 10 µg L(-1) for Cu(2+), Co(2+), Ni(2+) and Fe(3+) respectively. The OSC-PLS1 for Cu(2+) and Ni(2+), the PLS1 for Co(2+) and the PC-FFANN for Fe(3+) were selected as the best models. The selected models were successfully applied for the simultaneous determination of elements in some foodstuffs and vegetables.

Ultrasound promoted facile synthesis of some pentafluoropyridine derivatives at ambient conditions.

Some pentafluoropyridine derivatives have been synthesized by the reaction of pentafluoropyridine with appropriate mono and bidentate nucleophile under ultrasonic irradiation. This new methodology provides good to excellent yields in short reaction times (25-120 min) at room temperature.