Synthesis,stereochemistry and anti-tetrabenazine activity of bicyclo analogues of 2-phenylmorpholines

A series of bicyclo analogues of several 2-phenylmorpholines were synthesized and tested for anti-tetrabenazine activity in mice. Most of the target compounds were prepared by reaction of 2-bromopropio-phenone ( 22 ) with the appropriate amino alcohol to form 2-phenylmorpholinols. Reduction of the 2-phenyl-morpholinols with sodium borohydride gave amino diols, which were cyclized to morpholines with acid. Alternatively, oxazines 17 and 18 were synthesized by alkylation of phenyl-(2-pyrrolo)carbinol (32a) and phenyl-(2-piperidyl)carbinol (32b) with 2-bromoethanol, followed by cyclization of the resulting amino diols with acid. Only the spirocyclic compounds 8 and 9 had i.p. anti-tetrabenazine activity comparable to the non-cyclic compounds 2a-3b , but 8 and 9 were less active by the oral route of administration.     

Analysis of collisional alignment and orientation studied by scattering of spin-polarized electrons from laser excited atoms

A general framework using density matrices is developed for the analysis of atomic excitation by spin-polarized electrons. This framework is applied to the specific case of the 3S _1/2→3P _3/2 transition in Na, as studied by the time-reversed, superelastic process. The scattering is characterized in terms of physical parameters describing the collisionally excitedp-state, i.e., its angular momentum (L _⊥), linear polarization (P _lin), and alignment angle (γ), with these parameters defined separately for singlet and triplet excitation. An expression for the scattering intensity is derived which is valid for arbitrary electron polarization and atomic state preparation. Specific examples are discussed with a view toward complete determination of the relevant scattering amplitudes and phases. Recent experimental results are reevaluated for comparison with theoretical calculations, and suggestions are made for future experiments.     

Synthesis of bis(arylsuh'onyl)furoxans from aryl nitromethyl sulfones

The synthesis of some symmetrically substituted bis(arylsulfonyl)furoxans from aryl nitromethyl sulfones is reported.     

Conformationally gated switching between superexchange and hopping within oligo-p-phenylene-based molecular wires

We observe well-defined regions of superexchange and thermally activated hopping in the temperature dependence of charge recombination (CR) in a series of donor-bridge-acceptor (D-B-A) systems, where D = phenothiazine (PTZ), B = p-phenylene (Ph(n)), n = 1-4, and A = perylene-3,4:9,10-bis(dicarboximide) (PDI). A fit to the thermally activated CR rates of the n = 3 and n = 4 compounds yields activation barriers of 1290 and 2030 cm(-1), respectively, which match closely with theoretically predicted and experimentally observed barriers for the planarization of terphenyl and quaterphenyl. Negative activation of CR in the temperature regions dominated by superexchange charge transport is the result of a fast conformational equilibrium that increasingly depopulates the reactive state for CR as temperature is increased. The temperature dependence of the effective donor-acceptor superexchange coupling, V(DA), measured using magnetic field effects on the efficiency of the charge recombination process, shows that CR occurs out of the conformation with lower V(DA) via the energetically favored triplet pathway.     

Increased efficacy of in vitro Photofrin photosensitization of human oral squamous cell carcinoma by iron and ascorbate

Photofrin^®, a photosensitizer used in the photodynamic therapy of cancer, selectively localizes in cellular membranes. Upon exposure to visible light, Photofrin^® produces singlet oxygen (¹O₂), which reacts with membrane polyunsaturated fatty acids forming lipid hydroperoxides. Transition metals, such as Fe²⁺, catalyze the production of cytotoxic free radicals from lipid hydroperoxides. Ascorbate reduces ferric to ferrous iron, further augmenting lipid peroxidation. Therefore, to increase the efficacy of Photofrin^® photosensitization, we added 20 μM ferrous sulfate and 100 μM ascorbic acid, in an aqueous layer over SCC-25 oral squamous cell carcinoma cells during in vitro illumination. In electron paramagnetic resonance spin trapping experiments, using POBN (-(4-pyridyl-1-oxide)-N-tert-butylnitrone), we observed that the presence of this pro-oxidant combination greatly increases the production of membrane-derived lipid free radicals. The effect was time dependent but only partially concentration dependent. Trypan blue dye exclusion demonstrated that this increase in lipid radical formation correlated with cytotoxicity. These observations support the hypothesis that Photofrin^® photosensitization leads to lipid hydroperoxide formation, which increases the cell's susceptibility to iron-induced Fenton chemistry. The resulting free radical-mediated lipid peroxidation results in cell death. From these data we hypothesize that the efficacy of photodynamic therapy of superficial cancer might be increased by the topical application of the pro-oxidant combination of iron and ascorbate. Furthermore, their use will probably allow lower doses of Photofrin^® without compromising antitumor effect.     

Mechanistic Studies of the Biosynthesis of 3,6-Dideoxysugars in Bacteria: Exploration of a Novel C-O Bond Cleavage Event

Deoxy sugars are ubiquitous in nature and contribute to diverse biological activities. Attempts to design systems to control or to mimic their functions are hampered, however, by the lack of biosynthetic knowledge of these unique sugars. To elucidate the mechanism by which the sugar deoxygenation is effected, we have initiated a study to explore the biosynthesis of CDP-ascarylose, a 3,6-dideoxyhexose found in the lipopolysaccharides of Yersinia pseudotuberculosis, and our initial focus centered on C-3 deoxygenation catalyzed by E₁ and E₃. We have now purified the wild-type enzymes, cloned the corresponding genes (ascC for E₁ and ascD for E₃), and overexpressed the gene products in Escherichia coli. The purified E₃ is a flavoprotein comprising an iron-sulfur center and E₁ is an iron-sulfur containing, pyridoxamine 5′-phosphate-de-pendent enzyme. Since these iron-sulfur clusters are well known one-electron carriers, reactions mediated by E₁ and E₃ must proceed via a radical mechanism. Recently, EPR analysis of E₁/E₃ catalysis indicated a potential new redox role for pyridoxamine as a cofactor. These findings make this system unique from two perspectives: E₁ is the only coenzyme B₆-dependent catalyst that interacts with a sugar and not with an amino acid, and it is the first example in which coenzyme B₆ may facilitate one-electron redox chemistry. Thus, the unprecedented mechanisms of E₁ and E₃ distinguish this system as a novel radical deoxygenation with potentially interesting future developments.     

Novel 3-phenylprop-2-ynylamines as inhibitors of mammalian squalene epoxidase

The synthesis of a novel series of 3-phenylprop-2-ynylamines as selective mammalian squalene epoxidase inhibitors is described. Structure activity relationship studies led to the discovery of compound 19, 1-[3-(3,5-dichlorophenyl)-prop-2-ynyl]-3- methylpiperidine hydrochloride with an IC50 of 2.8 +/- 0.6 microM against rat liver squalene epoxidase. Against 23 strains of fungal squalene epoxidase compound 19 was found to be inactive.