The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase

Various aza-analogues of 1,4-naphthoquinone and menadione were prepared and tested as inhibitors and substrates of the plasmodial thioredoxin and glutathione reductases as well as the human glutathione reductase. The replacement of one to two carbons at the phenyl ring of the 1,4-naphthoquinone core by one to two nitrogen atoms led to an increased oxidant character of the molecules in accordance with both the redox potential values and the substrate efficiencies. Compared to the 1,4-naphthoquinone and menadione, the quinoline-5,8-dione 1 and both quinoxaline-5,8-diones 5 and 6 behaved as the most efficient subversive substrates of the three NADPH-dependent disulfide reductases tested. Modulation of these parameters was observed by alkylation of the aza-naphthoquinone core.     

Resonance strategies for the belting style: Results of a single female subject study

This study explores resonance strategies used for the belting style and associated vocal fold vibratory patterns, for the vowels /e/, /a/, /i/, and /u/ on G4 and B4-flat. Acoustic spectra of belted vowels and their unoptimized, "speech-like" equivalents were compared. Vocal fold vibratory patterns were quantified using electroglottography. Results show that /a/ is inherently suitable for belting and requires no adjustment. For /e/, F2-H5 tuning was observed. For /i/, F1 was detuned from H1, enhancing also H2. For /u/, both F1 and F2 were raised to accomplish F2-H3 tuning. These results show that the loud, bright sound of the belting style is achieved by the implementation of resonance strategies that enhance higher harmonics. Electroglottography revealed that resonance strategies also result in raising the closed quotient (CQ) above 52%, an apparent threshold value for belting.     

A convenient biomimetic synthesis of optically active putative neurotoxic metabolites of MDMA ("ecstasy") from R-(-)- and S-(+)-N-methyl-α-methyldopamine precursors

(±)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates. As yet, chirality of MDMA was not considered in previously reported in vivo studies because HHMA was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the total synthesis of enantiomerically pure precursors, R-(-)-HHMA and S-(+)-HHMA, was envisioned with the ultimate goal to prepare substantial amounts of optically active thioether conjugates. Recently, we reported the first total synthesis of the R-enantiomer. In this paper, a novel synthesis of the S-enantiomer is described, in 45% overall yield (six steps) and 99% ee, using commercially available l-Boc-alanine (99% ee) as the chiral source. Having at our disposal suitable amounts of R-(-)-HHMA and S-(+)-HHMA precursors, a straightforward one-pot electrochemical procedure has been further developed for the synthesis of several catechol-thioether conjugates in acceptable yields (40-53%) and high degree of purity (99%), with complete diastereoselectivity. The availability of these newly synthesized optically active catechol-thioether conjugates is crucial for ongoing future in vivo studies about their role in MDMA neurotoxicity.     

Study of the Lithiated Phenylacetonitrile Monoanions and Dianions Formed According to the Lithiated Base Used (LHMDS, LDA, or n-BuLi). 2. Alkylation and Deuteriation Mechanism Study by Vibrational and NMR Spectroscopy and Quantum Chemistry Calculations

Mechanisms of alkylation by PhCH(2)Cl or CH(3)I in THF and of deuteriation by DCl (4 N in D(2)O) in THF or THF-toluene of lithiated phenylacetonitrile monoanions and dianions obtained with LHMDS, LDA, or n-BuLi are studied by vibrational and NMR spectroscopy and quantum chemistry calculations. Dialkylation of the three dilithio dianions generated with n-BuLi (2.0-2.7 equiv, THF-hexane) depends on their structure: N-lithio (PhCCNLi)(-)Li(+) and (C,N)-dilithio PhCLiCNLi dianions afford PhCR(2)CN (R = PhCH(2), CH(3)) from the intermediate N-lithio monoalkylated monoanion PhCRCNLi 10; C-lithio dianion (PhCLiCN)(-)Li(+) leads to a carbenoid species, the C-lithio monoalkylated nitrile PhCLiRCN 11, which either eliminates carbene Ph-C?-R and different LiCN species or isomerizes to PhCRCNLi in the presence of LiX (X = Cl, I). Dialkylation or dideuteriation of monoanions (monomers, dimers, and heterodimers [PhCHCNLi·LiR'], R' = (SiMe(3))(2)N, (i-Pr)(2)N) obtained with LHMDS or LDA (2.4 equiv, THF) proceeds via a sequential mechanism involving monometalation-monoalkylation (or monodeuteriation) reactions. Some carbene and (LiCNLi)(+) are also observed, and explained by another mechanism implying the C-lithio monoalkylated monoanion PhCLiRCN 9 in the presence of LiX. These results show the ambiphilic behavior of PhCLiRCN as a carbenoid (11) or a carbanion (9) and the importance of LiX formed in situ in the first alkylation step.     

Novel access to 1,4-benzodiazepin-2-ones via the Buchwald reaction and application to the synthesis of novel heterocyclics

A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been developed starting from the 2-halogenobenzophenone under Buchwald conditions (Pd(OAc)₂, XantPhos, Cs₂CO₃, dioxane 100 °C). This strategy has been extended to two 2-halogeno-3-benzoyl-azines (pyridines, pyridazines).     

Experimental structure determination of silver cluster ions (Ag(n) +, 19 < or = n < or = 79)

The structures of mass selected silver cluster cations Ag19 +, Ag38 +, Ag55 +, Ag59 +, Ag75 +, and Ag79 + have been probed at a temperature of 100 K by trapped ion electron diffraction. The structure assignment is carried out by comparison of the experimental scattering intensity with theoretical scattering functions of calculated candidate structures obtained by density functional theory. For the cluster sizes studied the resulting experimental data are invariably best described by structures based on the icosahedral motif, while closed packed structures can be ruled out.     

The Weierstrass Subgroup of a Curve has Maximal Rank

We show that the Weierstrass points of the generic curve ofgenus g over an algebraically closed field of characteristic0 generate a group of maximal rank in the Jacobian. 2000 MathematicsSubject Classification 11G30, 14H40, 14H10, 14H55, 14Q05.     

Cyclizations in hyperbranched aliphatic polyesters and polyamides

Hyperbranched aliphatic polyesters of 2,2′-bis-(hydroxymethyl) propanoic acid and hyperbranched aliphatic polyamides obtained from new carboxy- and amino-functionalized caprolactams were studied by NMR spectroscopy and MALDI-TOF mass spectrometry. Ring-chain equilibria taking place through intramolecular hydroxy-ester, carboxy-amide or amine-amide interchanges and leading to the formation of cyclic branches or end-groups were found to exert a predominant influence on the molar mass of these hyperbranched polymers. A number of intra- or intermolecular side reactions, such as the formation of ethers in polyesters and the formation of anhydrides, imides, amidines and secondary amines in polyamides were also detected and resulted in polymer crosslinking on prolonged heating. The existence of such ring-chain equilibria and side-reactions make the control of hyperbranched polymer structure much more difficult than generally accepted.