A Greener and Efficient Method for Nucleophilic Aromatic Substitution of Nitrogen-Containing Fused Heterocycles.

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only five minutes.

First Metal-Free Synthesis of Tetracyclic Pyrido and Pyrazino Thienopyrimidinone Molecules.

We report herein a new metal free synthetic pathway to generate tetracyclic compounds from 3-aminothieno[3,2-b]pyridine-2-carboxylate. To enlarge the molecular diversity, we studied the Suzuki coupling of 9-chloro-6H-pyrido[1,2-a]pyrido[2',3':4,5]thieno[3,2-d]pyrimidin-6-one and several boronic acids were easily introduced.

Comparison of 2-Aminopyridine and 4-Thiopseudisocytosine PNA Nucleobases for Hoogsteen Recognition of Guanosine in RNA.

Peptide nucleic acid (PNA) is emerging as a promising ligand for triple-helical recognition of folded biologically relevant RNA. Chemical modifications are actively being developed to achieve high affinity and sequence specificity under physiological conditions. In this study, we compared two modified PNA nucleobases, 2-aminopyridine (M) and 4-thiopseudisocytosine (L), as alternatives to protonated cytosine (unfavorable under physiological conditions), to form more stable triplets than C+·G-C. Both nucleobases formed M+·G-C and L·G-C triplets of similar stability; however, the L-modified PNAs showed somewhat reduced sequence specificity. In conclusion, M and L represent two alternative solutions to the problem of cytosine protonation in triple-helical recognition of RNA. In M, the pKa is increased to favor partial protonation, which improves solubility and cellular uptake of M-modified PNAs. In L, the sulfur substitution enhances favorable hydrophobic interactions, which may have advantages in avoiding off-target effects that may be caused by cationic modifications. However, our results showed that substituting Ms with Ls did not restore the sequence specificity of a PNA containing cationic groups.

Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in NMDA-Induced Excitotoxicity.

N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole derivatives of tomentosin were prepared and tested for their protective and anti-apoptotic effects in NMDA-induced excitotoxicity. Amino-tomentosin derivatives were generated through a diastereoselective conjugate addition of several secondary amines to the α-methylene-γ-butyrolactone function, while the 1,2,3-triazolo-tomentosin was prepared by a regioselective Michael-type addition carried out in the presence of trimethylsilyl azide (TMSN3) and the α-methylene-γ-lactone function. The intermediate key thus obtained underwent 1,3-dipolar Huisgen cycloaddition using a wide range of terminal alkynes. The possible effects of the derivatives on cell viability and free-radical production following NMDA treatment were measured by Water-Soluble Tetrazolium Salts (WST-1) and Dichlorofluorescein Diacetate (DCF-DA) assays, respectively. The alterations in apoptosis-related proteins were examined by Western blot technique. Our study provides evidence that synthesized triazolo- and amino-tomentosin derivatives show neuroprotective effects by increasing cellular viability, decreasing ROS production, and increasing the Bcl-2/Bax ratio in NMDA-induced excitotoxicity. The findings highlight particularly 2e, 2g, and 6d as potential regulators and neuroprotective agents in NMDA overactivation.

Pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5-amines as Potential Cytotoxic Agents against Human Neuroblastoma.

We report herein the evaluation of various pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multicomponent Groebke-Blackburn-Bienaymé reaction to yield various pyrido[2',1':2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer potential of these pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5-amine derivatives in the human neuroblastoma cell line, the cytotoxicity was examined using the WST-1 assay after 72 h drug exposure. A clonogenic assay was used to assess the ability of treated cells to proliferate and form colonies. Protein expressions (Bax, bcl-2, cleaved caspase-3, cleaved PARP-1) were analyzed using Western blotting. The colony number decrease in cells was 50.54%, 37.88% and 27.12% following exposure to compounds 2d, 2g and 4b respectively at 10 µM. We also show that treating the neuroblastoma cell line with these compounds resulted in a significant alteration in caspase-3 and PARP-1 cleavage.

Electrostatic Interaction-Induced Formation of Enzyme-on-MOF as Chemo-Biocatalyst for Cascade Reaction with Unexpectedly Acid-Stable Catalytic Performance.

Combining biocatalytic and chemocatalytic reactions in a one-pot reaction not only avoids the tedious isolation of intermediates during the reactions but also provides a desirable alternative to extend the range of catalytic reactions. Here, we report a facile strategy to immobilize an enzyme, glucose oxidase (GOx), on PCN-222(Fe) induced by electrostatic interaction in which PCN-222(Fe) serves as both a support and chemocatalyst. The immobilization was confirmed through ζ potential measurement, confocal laser scanning microscopy, Fourier transform infrared spectrometry, and UV-vis spectroscopy. This chemo-biocatalyst was applied to a cascade reaction to catalyze glucose oxidation and ABTS (ABTS = 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (or pyrogallol) oxidation. The catalytic kinetics studies show that these chemo-biocatalytic cascade reactions obey the Michaelis-Menten equation, which indicates that the cascade reactions follow the typical enzymatic dynamic regulation process. Interestingly, GOx/PCN-222(Fe) exhibits an exceptional acid-stable catalytic performance as evidenced by circular dichroism spectroscopy where no significant structure change was observed toward acidic solutions with different pH values. GOx/PCN-222(Fe) also displays desirable recyclability since no significant loss of conversion rates was found after six repeated reactions. This work presents a convenient strategy to construct metal-organic framework based chemo-biocatalysts, which may find potential applications in sensing and nanomachines.

Unusual rearrangement of imidazo[1,5-a]imidazoles and imidazo[1,2-b]pyrazoles into imidazo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines.

A multicomponent reaction giving easy and cheap access to a variety of bicyclic 5,5-fused hetero-rings has been developed. Then, an usual rearrangement of imidazo[1,5-a]imidazoles or imidazo[1,2-b]pyrazoles leading to bi-heterocyclic imidazo- and pyrazolo[1,5-a]pyrimidines in the presence of a specific amount of I2 in THF at room temperature has been achieved. This new method enables the hitherto unreported synthesis of functionalized imidazo- and pyrazolo[1,5-a]pyrimidines.

Efficient synthesis and first regioselective C-6 direct arylation of imidazo[2,1-c][1,2,4]triazine scaffold and their evaluation in H2O2-induced oxidative stress.

Oxidative stress and apoptosis are both associated with various acute and chronic disorders. Thus, the aim of the present study is to synthesize imidazo[2,1-c][1,2,4]triazines derivatives and to evaluate their effects in H2O2-induced oxidative stress in human neuroblastoma cell line (SH-SY5Y cells). The effects of the compounds on cell viability were measured by MTT assay and the changes in stress and apoptosis-related proteins were investigated by PathScan® Stress and Apoptosis Signaling Antibody Array kit and Western Blot technique. In particular, four compounds were found to protect SH-SY5Y cells from H2O2-induced toxicity by increasing Bcl-2/Bax ratio, regulating PI3-K/Akt cascade and inhibiting the ERK pathway.

Synthesis of new heterocyclic compounds based on pyrazolopyridine scaffold and evaluation of their neuroprotective potential in MPP+-induced neurodegeneration.

Neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease affect millions of people in the world. Thus several new approaches to treat brain disorders are under development. The aim of the present study is to synthesize potential neuroprotective heterocyclic compounds based on pyrazolopyridine derivatives and then to evaluate their effects in MPP+-induced neurodegeneration in human neuroblastoma cell line (SH-SY5Y cells). The effects of the compounds on cell viability were measured by MTT assay and the changes in apoptosis-related proteins including bax, Bcl-2, Bcl-xl and caspase-3 were investigated by western blot technique. Based on the cell viability results obtained by MTT assay, the percentage of neuroprotection-induced by compounds against MPP+-induced neurotoxicity in SH-SY5Y cells was between 20% and 30% at 5 µM concentrations of all synthesized compounds. Moreover, the downregulation in pro-apoptotic proteins including bax and caspase-3 were found following the novel synthesized compounds treatments and these effects were observed in a dose-dependent manner. Our results provide an evidence that these heterocyclic compounds based on pyrazolopyridine derivatives may have a role on dopaminergic neuroprotection via antiapoptotic pathways.