Synthesis of selenazoles by in situ cycloisomerization of propargyl selenoamides using oxygen-selenium exchange reaction.

Herein, we describe an approach toward selenazole preparation based on the cycloisomerization of propargyl selenoamides. The selenoamides were synthesized in situ using the Ishihara reagent with spontaneous cyclization to form the 2,5-disubstituted selenazoles. Heterocylcles 9a-j were prepared using readily available starting materials, and yields ranged from moderate to good (20-80%). Methylselenazole 9a could be transformed into a bromomethyl derivative 13 using NBS. The intermediate 13 would provide a more versatile building block for further derivatizations, e.g., the cyanide 14.

Synthesis and biological evaluation of Foscan® bile acid conjugates to target esophageal cancer cells.

Porphyrins and chlorins such as Foscan® have a natural proclivity to accumulate in cancer cells. This trait has made them good candidates for photosensitizers and as imaging agents in phototherapy. In order to improve on cellular selectivity to lower post-treatment photosensitivity bile acid porphyrin bioconjugates have been prepared and investigated in esophageal cancer cells. Bile acids which are known to selectively bind to, or be readily taken up by cancer cells were chosen as targeting moieties. Synthesis of the conjugates was achieved via selective nucleophilic monofunctionalization of 5,10,15,20-tetrahydroxyphenylporphyrins with propargyl bromide followed by Cu(I) mediated cycloaddition with bile acid azides in good yields. The compounds were readily taken up by esophageal cancer cells but showed no PDT activity.

Copper-mediated aerobic synthesis of 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles from N-allyl/propargyl enamine carboxylates.

Synthetic methods for 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles have been developed that use copper-mediated/catalyzed reactions of N-allyl/propargyl enamine carboxylates under an O(2) atmosphere and involve intramolecular cyclopropanation and carbooxygenation, respectively. These methodologies take advantage of orthogonal modes of chemical reactivity of readily available N-allyl/propargyl enamine carboxylates; the complementary pathways can be accessed by slight modification of the reaction conditions.

Iododerivative of pargyline: a potential tracer for the exploration of monoamine oxidase sites by SPECT.

Monoamine oxidases are important in the regulation of monoaminergic neurotransmission. An increase in monoamine oxidase B (MAO B) has been observed in some neurodegenerative diseases, and therefore quantification of cerebral MAO B activity by SPECT would be useful for the diagnosis and therapeutic follow-up of these disorders. We have developed an iodinated derivative of pargyline, a selective inhibitor of MAO B, in order to explore this enzyme by SPECT. Stable bromo and iodo derivatives of pargyline were synthesized and chemically characterized. The radioiodinated ligand [125I]-2-iodopargyline was obtained with high specific activity from the bromo precursor by nucleophilic exchange. Affinity and selectivity of 2-iodopargyline were tested in vitro. Biodistribution study of [125I]-2-iodopargyline was performed in rats. Radioiodinated ligand were obtained in a no-carrier-added form. 2-iodopargyline has a higher in vitro affinity for MAO B than pargyline. However, the in vitro selectivity for MAO B was better for pargyline than for 2-iodopargyline. Ex vivo autoradiographic studies and in vivo saturation studies with selective inhibitors of MAO showed that the cerebral biodistribution of [125I]-2-iodopargyline in the rat is consistent with high level binding to MAO B sites in the pineal gland and in the thalamus. In conclusion, 2-iodopargyline preferentially binds in vivo to MAO B sites with high affinity. However, its selectivity for MAO B in rats is not very high, whereas this ligand binds to a lesser extent to MAO A. It will be then of great value to evaluate the specificity of 2-iodopargyline in humans. This new ligand labeled with 123I should therefore be a suitable tool for SPECT exploration of MAO B in the human brain.

Neurochemical and neuroprotective effects of some aliphatic propargylamines: new selective nonamphetamine-like monoamine oxidase B inhibitors.

Aliphatic N-propargylamines have recently been discovered to be highly potent, selective, and irreversible monoamine oxidase B (MAO-B) inhibitors. N-Methyl-N-(2-pentyl)propargylamine (M-2-PP) and N-methyl-N-(2-hexyl) propargylamine (2-HxMP), for example, are approximately fivefold more potent that l-deprenyl at inhibiting mouse brain MAO-B activity following oral administration. These inhibitors are nonaromatic compounds and are chemically quite different from other known MAO-B inhibitors. Some of their neurochemical and neuroprotective properties have been evaluated and compared with those of l-deprenyl. We have confirmed that these new inhibitors selectively inhibit MAO-B activity both in vitro and in vivo. 2-Phenylethylamine levels were substantially increased following administration of M-2-PP, but the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were not affected except at high, nonselective doses. Chronic oral administration of l-deprenyl and M-2-PP causes selective inhibition of MAO-B activity and increases dopamine levels in mouse caudate. M-2-PP, like l-deprenyl, has been shown to be potent in protecting against MPTP-induced damage in the mouse. N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenaline neurotoxin, is not an MAO substrate. Its noradrenaline-depleting effects were substantially mitigated by l-deprenyl as well as by M-2-PP and 2-HxMP in the mouse hippocampus. Administration of 2-phenylethylamine, however, failed to reverse the effect of DSP-4. The neuroprotective effect of M-2-PP and 2-HxMP is apparently unrelated to the uptake of DSP-4.

In vitro toxicity test of poisonous mushroom extracts with isolated rat hepatocytes.

Effects of poisonous mushroom extracts on isolated rat hepatocytes were studied. Though no significant decrease in the cell viability was observed during the incubation of hepatocytes with the extracts at a concentration of 5% (v/v) of Amanita abrupta, A. gymnopus, and A. virosa caused marked decreases in the intracellular glutathione content in sharp contrast to the extracts of A. volvata and A. flavipes. Comparative toxicity tests were carried out for the effects of the extract of A. abrupta, dl-propargylglycine, and alpha-amanitin. The extract of A. abrupta at a concentration of 1% (v/v) caused a marked decrease in the glycogen content, a noticeable elevation in the phosphorylase alpha activity, and a slight acceleration of lipid peroxidation in the hepatocytes. Although dl-propargylglycine decreased the intracellular glutathione content progressively with the incubation time, a significant effect of the chemical on lipid peroxidation and the glycogen content was observed only after prolonged incubation at a concentration of 5 mM. On the other hand, alpha-amanitin exerted a little effect on the hepatocytes at 1 microM. These results have indicated that the intoxication by the extract of A. abrupta on the hepatocytes might not due to independently each component, dl-propargylglycine and alpha-amanitin, but combined effect of these components or unidentified substances.