A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson's Disease

We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.Peer reviewe

3,1,2,4-Benzothiaselenadiazine and related heterocycles: synthesis and transformation into Herz-type radicals

The archetypal 3,1,2,4-benzothiaselenadiazine, its 5- and 8-Me3Si derivatives and related dithiadiazine and trithiadiazepine were synthesized from 2-Me3SiC6H4N=S=NSiMe3 by the action of SeCl2, SeCl4, SCl2, and S2Cl2 and converted into persistent 2,1,3-benzothiaselenazolyl and 1,2,3-benzodithiazolyl radicals characterized by EPR spectroscopy and DFT calculations

3,1,2,4-Benzothiaselenadiazine and related heterocycles: synthesis and transformation into Herz-type radicals

The archetypal 3,1,2,4-benzothiaselenadiazine, its 5- and 8-Me3Si derivatives and related dithiadiazine and trithiadiazepine were synthesized from 2-Me3SiC6H4N=S=NSiMe3 by the action of SeCl2, SeCl4, SCl2, and S2Cl2 and converted into persistent 2,1,3-benzothiaselenazolyl and 1,2,3-benzodithiazolyl radicals characterized by EPR spectroscopy and DFT calculations

Protonation Behavior of 1,1′-Bi-2-naphthol and Insights into Its Acid-Catalyzed Atropisomerization

The behavior of 1,1′-bi-2-naphthol (BINOL) in variety of (super)­acid media has been studied by NMR. The results are combined with the theoretical (DFT) study of the role of mono- and diprotonated forms of BINOL in the acid-catalyzed atropisomerization of this compound. It is demonstrated that the process of enantiomeric configuration exchange proceeds mainly via internal rotation around the C1­(sp³)–C1′(sp³) bond in intermediates such as C1-monoprotonated keto or C1,C1′-diprotonated forms of BINOL, depending on the acidity level

NMR and EPR Study of Homolysis of Diastereomeric Alkoxyamines

Three alkoxyamines based on imidazoline radicals with a pyridine functional group—potential initiators of nitroxide-mediated, controlled radical polymerization—were synthesized. Electron Paramagnetic Resonance (EPR) measurements reveal biexponential kinetics for the thermolysis for diastereomeric alkoxyamines and monoexponential kinetics for an achiral alkoxyamine. For comparison, the thermolysis of all three alkoxyamines was studied by NMR in the presence of three different scavengers, namely tetramethylpiperidine-N-oxyl (TEMPO), thiophenol (PhSH), and β-mercaptoethanol (BME), and detailed analysis of products was performed. NMR differentiates between N-inversion, epimerization, and homolysis reactions. The choice of scavenger is crucial for making a reliable and accurate estimate of the true homolysis rate constant

Synthesis of Nitro- and Acetyl Derivatives of 3,7,10-Trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane

Here, we report the study results of the nitration of 3,7,10-trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane (THAP) by different nitrating agents such as nitric acid, mixed nitric/sulfuric acids, nitric anhydride, and mixed concentrated nitric acid/acetic anhydride to furnish 3,7,10-trioxo-2-nitro-2,4,6,8,9,11-hexaaza[3.3.3]propellane and 3,7,10-trioxo-2,8-dinitro-2,4,6,8,9,11-hexaaza[3.3.3]propellane, whereas a lactam–lactim rearrangement was found to take place upon vigorous cooling to give 10-hydroxy-2,4,6,8,9,11-hexaazatricyclo[3.3.3.01,5]undec-9-ene-3,7-dione. The two competing reactions, lactam–lactim rearrangement, and nitration were found to take place. The acylation of 3,7,10-trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane was examined and the formation conditions of 2,6-di- and 2,6,9-triacetyl-substituted and 3,7,10-trioxo-2,4,6,8,9,11-hexaacetyl-2,4,6,8,9,11-hexaaza[3.3.3]propellane were established. The acetyl derivatives were found to be instable in an acidic medium and to undergo deacylation. The obtained findings correlate well with the quantum-chemical calculations