Nitroxyl Hybrids with Curcumin and Stilbene Scaffolds Display Potent Antioxidant Activity, Remodel the Amyloid Beta Oligomer, and Reverse Amyloid Beta-Induced Cytotoxicity.

The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer's disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade.

A New Application of Spin and Fluorescence Double-Sensor Molecules.

EPR imaging techniques are known to be successful tools for mapping living bodies, especially because of the high transparency of tissues in the microwave range. This technique assumes the presence of radicals whose in vivo transport is also controlled by serum albumins. Accordingly, in this study, the interactions between 3-hydroxymethyl-1-oxyl-4-(pyren-1-yl)-2,2,5,5-tetramethyl-2,5-dihydro-1-pyrrole radical and the human serum albumin molecules were investigated.

Phase-Selective Synthesis of Anatase and Rutile TiO Nanocrystals and Their Impacts on Grapevine Leaves: Accumulation of Mineral Nutrients and Triggering the Plant Defense.

Titanium dioxide nanocrystals (TiO NCs), through their photocatalytic activity, are able to generate charge carriers and induce the formation of various reactive oxygen species (ROS) in the presence of O and HO. This special feature makes TiO an important and promising material in several industrial applications. Under appropriate antioxidant balancing, the presence of ROS is crucial in plant growth and development, therefore, the regulated ROS production through the photocatalytic activity of TiO NCs may be also exploited in the agricultural sector.

Comparative EPR Study on the Scavenging Effect of Methotrexate with the Isomers of Its Photoswitchable Derivative.

The scavenging effect of the antimetabolite dihydrofolate reductase inhibitor methotrexate (MTX) and the isomers of its photoswitchable derivate, - and -phototrexate (PHX), have been compared by ESR spectroscopy, with the application of a cyclic hydroxylamine spin probe. The results showed the most pronounced scavenging effect in the presence of -phototrexate (-PHX). At a low concentration (100 µM) -PHX also showed a greater scavenging effect than the parent molecule MTX.

Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine.

The reaction of a diene nitroxide precursor with dichlorophenylphosphine in a McCormac procedure afforded 1,1,3,3-tetramethyl-5-phenyl-1,2,3,4,5,6-hexahydrophospholo[3,4-c]pyrrole-5-oxide-2-oxyl. Lithiation of the protected 3-iodo-pyrroline nitroxide followed by treatment with chlorodiphenylphosphine after deprotection afforded (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1-pyrrol-3-yl)diphenylphosphine oxide, and after reduction, (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1-pyrrol-3-yl)diphenylphosphine was realized, which was also supported by X-ray single crystal diffraction measurements. This pyrroline diphenylphosphine derivative was converted to hexadecylphosphonium salt, which is an analogue of antineoplastic agent, MITO-CP.

Photocatalytic Inactivation of Plant Pathogenic Bacteria Using TiO Nanoparticles Prepared Hydrothermally.

Exploitation of engineered nanomaterials with unique properties has been dynamically growing in numerous fields, including the agricultural sector. Due to the increasing resistance of phytopathogenic microbes, human control over various plant pathogens in crop production is a big challenge and requires the development of novel antimicrobial materials. Photocatalytic active nanomaterials could offer an alternative solution to suppress the plant pathogens.

Syntheses and Reactions of Pyrroline, Piperidine Nitroxide Phosphonates.

Organophosphorus compounds occupy a significant position among the plethora of organic compounds, but a limited number of paramagnetic phosphorus compounds have been reported, including paramagnetic phosphonates. This paper describes the syntheses and further transformations of pyrroline and piperidine nitroxide phosphonates by well-established methods, such as the Pudovik, Arbuzov and Horner-Wadsworth-Emmons (HWE) reactions. The reaction of paramagnetic a-bromoketone produced a vinylphosphonate in the Perkow reaction.

Selective Induction of Cellular Toxicity and Anti-tumor Efficacy by N-Methylpiperazinyl Diarylidenylpiperidone and its Pro-nitroxide Conjugate through ROS-mediated Mitochondrial Dysfunction and G2/M Cell-cycle Arrest in Human Pancreatic Cancer.

Pancreatic adenocarcinoma is an aggressive cancer with poor clinical prognosis and limited therapeutic options. There is a significant lack of effective, safe, and targeted therapies for successful treatment of pancreatic cancer. In this report, we describe the anticancer efficacy of two novel compounds, N-methylpiperazinyl diarylidenylpiperidone (L-2663) and its pro-nitroxide conjugate (HO-4589) evaluated on human pancreatic adenocarcinoma (AsPC-1) cell line and xenograft tumor in mice.

Synthesis of Spin-Labelled Bergamottin: A Potent CYP3A4 Inhibitor with Antiproliferative Activity.

Bergamottin (BM, ), a component of grapefruit juice, acts as an inhibitor of some isoforms of the cytochrome P450 (CYP) enzyme, particularly CYP3A4. Herein, a new bergamottin containing a nitroxide moiety (SL-bergamottin, SL-BM, ) was synthesized; chemically characterized, evaluated as a potential inhibitor of the CYP2C19, CYP3A4, and CYP2C9 enzymes; and compared to BM and known inhibitors such as ketoconazole (KET) (3A4), warfarin (WAR) (2C9), and ticlopidine (TIC) (2C19). The antitumor activity of the new SL-bergamottin was also investigated.

Thermodynamic Characterization of the Interaction between the Antimicrobial Drug Sulfamethazine and Two Selected Cyclodextrins.

Sulfamethazine is a representative member of the sulfonamide antibiotic drugs; it is still used in human and veterinary therapy. The protonation state of this drug affects its aqueous solubility, which can be controlled by its inclusion complexes with native or chemically-modified cyclodextrins. In this work, the temperature-dependent (298-313 K) interaction of sulfamethazine with native and randomly methylated β-cyclodextrins have been investigated at acidic and neutral pH.

Interaction of Chrysin and Its Main Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide with Serum Albumin.

Chrysin (5,7-dihydroxyflavone) is a flavonoid aglycone, which is found in nature and in several dietary supplements. During the biotransformation of chrysin, its conjugated metabolites chrysin-7-sulfate (C7S) and chrysin-7-glucuronide (C7G) are formed. Despite the fact that these conjugates appear in the circulation at much higher concentrations than chrysin, their interactions with serum albumin have not been reported.

Antiproliferative Effect of a Novel 4,4'-Disulfonyldiarylidenyl Piperidone in Human Colon Cancer Cells.

The synthesis and antiproliferative effect of a novel curcumin analog, 4,4'-disulfonyldiarylidenyl piperidone, are reported. The design of the molecule is based on the fusion of an antiproliferative segment, namely diarylidenyl piperidone (DAP), with N-hyroxypyrroline, which is known to metabolically convert to nitroxide and protect healthy cells. Cellular uptake, metabolic conversion, cytotoxicity and antiproliferative effect of the DAP derivative against HCT-116 human colon cancer cells have been determined.

Nanostructured TiO-induced photocatalytic stress enhances the antioxidant capacity and phenolic content in the leaves of Vitis vinifera on a genotype-dependent manner.

Over the past decades, nanotechnology has received great attention and brought revolutionary solutions for a number of challenges in scientific fields. Industrial, agricultural and medical applications of engineered nanomaterials have increased intensively. The ability of titanium dioxide nanoparticles (TiO NPs) to produce reactive oxygen species (ROS), when excited by ultra-violet (UV) light, makes them useful for effectively inactivate various pathogens.

Synthesis and Biological Evaluation of Curcumin-Nitroxide-Based Molecular Hybrids as Antioxidant and Anti-Proliferative Agents.

Background: Natural products and their derivatives are widely used to treat cancer and other diseases associated with ROS- and RNS-induced damages.

Methods: A series of paramagnetic modified curcumin analogs and 3,5-diarylidene-piperidones (DAP) have been designed, synthesized, and characterized on their anti-proliferative and antioxidant activity.

Results: Biological characterization of the new compounds supported the earlier results that incorporation of a nitroxide moiety or its precursor into curcumin or diarylidenylpiperidone (DAP) scaffolds resulted in anti-proliferative effect toward cancerous cell-lines in case of aryl hydroxy and/or methoxy substituent containing derivatives, suggesting their potential for targeted therapeutic applications.

Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung.

Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH).

Synthesis and study of new paramagnetic and diamagnetic verapamil derivatives.

New derivatives of verapamil (1) modified with nitroxides and their precursors were synthesized and screened for reactive oxygen species (ROS)-scavenging activities. The basic structure was modified by changing the nitrile group to an amide or the methyl substituent on tertiary nitrogen with nitroxides and their reduced forms (hydroxylamine and secondary amines). Among the new verapamil derivatives compound 16B [Mohan, I.

Cardioprotection by HO-4038, a novel verapamil derivative, targeted against ischemia and reperfusion-mediated acute myocardial infarction.

Many cardiac interventional procedures, such as coronary angioplasty, stenting, and thrombolysis, attempt to reintroduce blood flow (reperfusion) to an ischemic region of myocardium. However, the reperfusion is accompanied by a complex cascade of cellular and molecular events resulting in oxidative damage, termed myocardial ischemia-reperfusion (I/R) injury. In this study, we evaluated the ability of HO-4038, an N-hydroxypiperidine derivative of verapamil, on the modulation of myocardial tissue oxygenation (Po(2)), I/R injury, and key signaling molecules involved in cardioprotection in an in vivo rat model of acute myocardial infarction (MI).

A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and necrotic cell death.

In ischemia-reperfusion injuries, elevated calcium and reactive oxygen species (ROS) induce mitochondrial permeability transition (mPT), which plays a pivotal role in mediating damages and cell death. Inhibition of mPT decreases necrotic cell death; however, during reperfusion, the continuous production of ROS may contribute to the temporary opening of the pore and thus the onset of the delayed apoptotic cell death. Based on amiodarone structure, we developed the first SOD-mimetic mPT inhibitor (HO-3538) that can eliminate ROS in the microenvironment of the permeability pore.

Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives.

Several amiodarone analogues were synthesized varying the 2-substituent on the benzofuran ring and diethylaminoethyl side chain of phenolether by introducing 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole and 1,2,5,6-tetrahydropyridine nitroxides or their amino or hydroxylamino precursors. The new compounds were screened on isolated mitochondria and perfused heart and their toxicity was evaluated on WRL-68 liver cells and H9C2 cardiomyocytes. Most of the newly synthesized derivatives exerted uncoupling effect on the mitochondrial oxidative phosphorilation at higher concentrations, compared to amiodarone and one of the modified amiodarone analogues showed an effect similar to that of amiodarone on the mitochondrial permeability transition and on restoring of mitochondrial high-energy phosphate metabolites in perfused hearts.