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O 10 de novembro de 2019 marcou mais uma ruptura institucional da história boliviana. Evo Morales renunciou ao seu mandato por pressões das Forças Armadas, justificadas pela convulsão social que assolou o país após o primeiro turno da eleição presidencial, em 20 de outubro. A Bolívia então viveu uma profunda crise política, que foi aprofundada pela pandemia decorrente do vírus Sars-Cov-2 (COVID-19). A proposta deste artigo é, em primeiro lugar, promover uma breve análise social dos Governo Morales a partir da cidade de El Alto e de suas organizações territoriais de base, uma vez que esta é considerada uma das principais bases sociais e políticas do governo. O intuito é observar mais especificamente como se deu uma crescente deterioração do apoio prestado ao governo. Na sequência, refletir sobre os meandros do processo que culmina na renúncia forçada do Presidente, buscando identificar se houve, de fato, um golpe de Estado em 2019 na nação andino-amazônica.

The reaction of primary nitroalkanes with magnesium or lithium amides provides a convenient, one-step synthesis of substituted amidoximes.

We discuss the potential use of multicomponent reactions in developing small-molecule probes of GABA A receptor function. Two examples that illustrate this approach are presented: the synthesis of a class of compounds that specifically modulate the function of GABA A receptors containing the δ-subunit, and also ‘caged’ GABA derivatives. A caged GABA is a photolabile precursor of GABA that releases GABA upon photolysis.

By generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-19th century when Strecker first produced alpha-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide. Recently, academic chemists have renewed their interest in MCRs. In part, the pharmaceutical industry has fueled this resurgence because of the growing need to assemble libraries of structurally complex substances for evaluation as lead compounds in drug discovery and development programs. The application of MCRs to that increasingly important objective remains limited by the relatively small number of such reactions that can be broadly applied to prepare biologically relevant or natural-product-like molecular frameworks. We were interested in applying logic-based approaches, such as our single reactant replacement (SRR) approach, as a way both to improve known MCRs and to design new multiple-component routes to bioactive structures. This Account provides several examples that illustrate the use of SRR with known MCRs as starting points for synthetic innovation in this area. As part of our working hypothesis, we initially explored strategies for engineering improvements into known MCRs, either by increasing the dimensionality--that is, changing an n-component to an (n + 1)-component reaction--or broadening the scope of useful input structures, or both. By exhaustively applying retrosynthetic analysis to the cognate MCR to identify and exploit alternative entry points into the overall reaction manifold, we have devised several such re-engineered MCRs. Serendipitous findings have also augmented the yield of useful developments from our logic-inspired approach. In some cases, we have identified surprising links between different compound families that provide useful new entry points for chemical library synthesis. In other cases, the same re-engineering logic made it possible (sometimes in unexpected ways) to transform certain nonelementary two-component reactions into higher order MCRs. While logic may also inspire the search for new MCRs, the design process requires added chemical creativity, which cannot be reduced to a simple formula. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis.

High densities of immobilized polymer brushes have been created on solid supports in a spatially addressable fashion. Octadecyltrichlorosilane was self-assembled on a silicon substrate to form an inert monolayer. The substrate was then patterned by low-energy electron beam lithography. Finally, the exposed region was back-filled with a second functionalized silane and the pattern was further amplified by surface-initiated ring-opening metathesis polymerization. The patterned substrate was imaged by scanning electron microscopy and atomic force microscopy.Key words: patterned thin film, e-beam lithography, ring-opening metathesis polymerization, polymer brushes.

New 3-component variations of the Fischer synthesis of substituted indoles have been developed based on the reaction of organometallic reagents with nitriles or carboxylic acids. The new variations expand the scope and synthetic utility of the method.

In an effort to develop potent multisubstrate-analog inhibitors of purine nucleoside phosphorylase (PNP), three nucleoside phosphonates were designed utilizing structural information from the previously reported structures of complexes of bovine PNP with substrates and products. The nucleoside phosphonates contain an acetal linkage at the O2' and O3' positions and a two-C-atom spacer between the ribose and phosphate moieties. The linkage enables the compounds to simultaneously occupy the purine-, ribose- and phosphate-binding sites. The chemical syntheses, inhibition profiles and structural characterization of these novel multisubstrate analog inhibitors with bovine PNP are described.

Human glutathione (GSH) transferase (hGSTP1-1) processes with similar kinetic efficiencies the antitumor agents 2-crotonyloxymethyl-2-cyclohexenone (COMC-6), 2-crotonyloxymethyl-2-cycloheptenone (COMC-7), and 2-crotonyloxymethyl-2-cyclopentenone (COMC-5) to 2-glutathionylmethyl-2-cyclohexenone, 2-glutathionylmethyl-3-glutathionyl-2-cycloheptenone, and 2-glutathionylmethyl-2-cyclopentenone, respectively. This process likely involves initial enzyme-catalyzed Michael addition of GSH to the COMC derivative to give a glutathionylated enol(ate), which undergoes nonstereospecific ketonization, either while bound to the active site or free in solution, to a glutathionylated exocyclic enone. Free in solution, GSH reacts at the exomethylene carbon of the exocyclic enone, displacing the first GSH to give the final product. This mechanism is supported by the observation of multiphasic kinetics in the presence of high concentrations of hGSTP1-1 and the ability to trap kinetically competent exocyclic enones in aqueous acid using COMC-6 and COMC-7 as substrates. That the exocyclic enone is formed by nonstereospecific ketonization of an enol(ate) species is indicated by the observation that COMC-6 (chirally labeled with deuterium at the exomethylene carbon) gives stereorandomly labeled exocyclic enone. The isozymes hGSTP1-1, hGSTA1-1, hGSTA4-4, and hGSTM2-2 catalyze the conversion of COMC-6 to final product with similar efficiencies (K(m) = 0.08-0.34 mM, k(cat) = 1.5-6.1 s(-)(1)); no activity was detected with the rat rGSTT2-2 isozyme. Molecular docking studies indicate that in hGSTP1-1, the hydroxyl group of Tyr108 might serve as a general acid catalyst during substrate turnover. The possible significance of these observations with respect to the metabolism of COMC derivatives in multidrug resistant tumors is discussed.

A one-pot reaction leading to the title compounds has been developed based on the in situ acylation and hydroxyarylation of 5-aminooxazoles at the 4-position of the heterocycle.

The Escherichia coli bifunctional T-protein transforms chorismic acid to p-hydroxyphenylpyruvic acid in the l-tyrosine biosynthetic pathway. The 373 amino acid T-protein is a homodimer that exhibits chorismate mutase (CM) and prephenate dehydrogenase (PDH) activities, both of which are feedback-inhibited by tyrosine. Fifteen genes coding for the T-protein and various fragments thereof were constructed and successfully expressed in order to characterize the CM, PDH and regulatory domains. Residues 1–88 constituted a functional CM domain, which was also dimeric. Both the PDH and the feedback-inhibition activities were localized in residues 94–373, but could not be separated into discrete domains. The activities of cloned CM and PDH domains were comparatively low, suggesting some cooperative interactions in the native state. Activity data further indicate that the PDH domain, in which NAD, prephenate and tyrosine binding sites were present, was more unstable than the CM domain.

[reaction: see text]. The effect of replacing the Brønsted acid in classic Passerini reactions with a mild Lewis acid has been studied. Triggered by metal-promoted silylation, condensations of aliphatic or aromatic carbonyl compounds with appropriately substituted isonitriles capable of neighboring group donation afford alpha-hydroxyamides, substituted oxazoles, and other useful heterocycles.

N - tert -Butylamides are readily converted into the corresponding carboxylic acids by simple nitrosation. The process, which occurs under mild nonaqueous conditions, leaves carboxylic esters untouched and transforms multicomponent reaction products into useful building blocks for further synthetic elaboration.

The oxidation of tosylmethylisocyanide affords the corresponding isocyanate (II) as white crystals that can be stored at -30°C for several weeks.

Several N-(3-phenylpropyl)-substituted spermidine and spermine derivatives were prepared and found to be potent competitive inhibitors of Trypanosoma cruzi trypanothione reductase (seven compounds with Ki values5 microM are described). The most effective inhibitor studied was compound 12 with a Ki value of 0.151 microM. Six of the compounds described are also effective trypanocides with IC50 values1 microM.

Benzyloxybutyryl (BOB) esters of alcohols can be prepared from commercially available 4-benzyloxybutyric acid by standard acylation techniques, by the Mitsunobu reaction (with inversion of configuration), or by the Jacobsen asymmetric nucleophilic ring opening of epoxides. BOB esters can be removed selectively in the presence of other esters under conditions that are compatible with a variety of sensitive functional groups.

Electrophilic additions to allylically substituted alkenes are of broad synthetic utility. The control of stereoselectivity in such reactions has attracted considerable interest. However, the effect of allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systematically. Studies on a series of mono, di-, and trisubstituted cyclopentenes are reported in which trans-vicinal-additions favor a syn-selective approach of electrophiles to the cyclopentene system. The formal addition of HOBr, HOCl, CH(3)SCl, and dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)/NaN(3) with a variety of cyclopentene substrates has been carried out, and the effects of various allylic substituents on these selectivities have been examined. Additions of HOBr, HOCl, and DMTSF to highly functionalized substrates proceed predictably with syn selectivity, giving predominantly or exclusively one product. Methanesulfenyl chloride additions are less predictable, but can be tuned by suitable alteration of solvent and substrate. Results have proven useful in total syntheses of (+)-trehazolin and (+)-allosamidin.

A stereoselective, chiral synthesis of the glyoxalase I inhibitor 2-crotonyloxymethyl-(4 R ,5 R ,6 R )-4,5,6-trihydroxycyclohex-2-enone 1 (COTC) from a simple derivative of (−)-quinic acid is described.

The cyclization of squalene catalyzed by the enzyme squalene-hopene cyclase (SHC) leads to the hopanoid family of pentacyclic triterpenes, which are widely found in bacteria as membrane constituents. SHC mediates a cascade of regio- and stereoselective cyclizations that has triggered considerable interest in understanding the enzyme's mechanism of action. This paper reports synthetic studies leading to the preparation of trienylamidrazone 8, trienylamidoxime 9, and tetraenylamidoxime 10 corresponding to a partially cyclized squalene chain. All three compounds displayed significant levels of inhibition when assayed against SHC, with 9 being more active than 8, and amidoxime 10 being the most potent. Detailed profiles of their inhibition kinetics are also presented.

Spider venom toxins have attracted considerable attention for their ability to block the action of excitatory amino acids such as glutamate and aspartate. A new neuroactive compound designated HF-7 was isolated in 1993 from the venom of a funnel-web spider, Hololena curta. HF-7 was shown to block kainate receptors and, albeit weakly, L-type calcium channels. Spectroscopic analysis established the structure of HF-7 as an unusual acetylated, disulfated fucopyranosyl guanosine, with the acetate ester attached at the 4-position of an α-linked fucose ring and two sulfates attached to the ribose ring. Because insufficient quantities of natural HF-7 were available for chemical degradation or X-ray diffraction analysis, total synthesis of three candidate structures was used to establish the identity of HF-7. Once HF-7 was fully characterized as 3‘-O-(4‘ ‘-O-acetyl-α-l-fucopyranosyl)guanosine-2‘,5‘-disulfate, an improved, targeted synthesis of the natural product was developed.

A four-component assembly of substituted di-O-acylglyceric acid amides has been developed from α-diazoketones. The process involves copper-catalyzed reaction of the α-diazoketone with a carboxylic acid, and subsequent Passerini condensation of the in situ formed α-acyloxyketone.

Bromocyclopentitols and amino (or amido) bromocyclopentitols having a CBr bond trans to two different vicinal hydroxyl groups show selectivity in base-promoted epoxide formation. The role of adjacent polar substituents in directing bromohydrin cyclization is discussed.

Syntheses of the title compounds ( 4 and 5 , respectively) are described together with a biogenetic hypothesis that rationalizes the origin of ceratinamine's unique cyanoformamide functionality.

Syntheses of pseudoceratidine and several analogs were developed in order to explore structure-activity relationships responsible for antifouling and antimicrobial activity.

Potent inhibitors of trehalase, such as trehazolin and its congeners, represent an attractive approach to the design of effective new insect control agents. In this report, enantioselective total syntheses of (−)-6-epitrehazolin and (+)-trehazolin were achieved using the asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene and the acylnitroso compound arising from in situ oxidation of (S)-mandelohydroxamic acid with tetrabutylammonium periodate. Further functionalization of the resulting 3,4,5-trisubstituted cyclopentene, either involving osmylation or epoxidation of the double bond, efficiently created pentasubstituted cyclopentanes. Introduction of the quaternary carbon in both synthesis targets was achieved via stereoselective osmylation of an intermediate 2,3,4,5-substituted 1-methylenecyclopentane.

New four- and five-component Ugi condensations have been developed based on the reaction of organometallic reagents with nitriles. These variations expand both the range of inputs and overall dimensionality of the method.

A convenient and efficient (one-step) oxidation is reported of commercially available tosylmethylisocyanide (TOSMIC) to form tosylmethylisocyanate, making this highly reactive bifunctional molecule a readily available synthetic reagent. Besides engaging in nucleophilic addition reactions with alcohols, amines, and thiols, tosylmethylisocyanate also reacts with carboxylic acids to form tosylmethylamides, which undergo substitution reactions in the presence of organocopper and organomagnesium reagents.

Thermodynamic parameters for E. coli chorismate mutase are reported. In addition, site-directed mutagenesis studies provide a direct mechanistic link to yeast chorismate mutase, further indicating the importance of entropic restriction and hydrogen bonding in the enzymic catalysis of Claisen rearrangements.

Analysis of the active-site residues of a fully functional chorismate mutase representing the N-terminal 113 amino acids of the Escherichia coli P-protein suggests that Lys39 and Gln88 play critical roles in catalyzing the rearrangement of chorismate to prephenate. Five site-directed mutants at these positions have been constructed in which Lys39 was replaced with Arg, Asn, and Gln, and Gln88 was replaced with Arg and Glu. Although the Gln88Arg plasmid failed to produce detectable cross-reacting proteins in E. coli, the other four plasmids were expressed, and the mutant proteins purified to homogeneity. Their structures were similar to wild type enzyme, as indicated by circular dichroism spectra, with Lys39Gln showing a small deviation. In accordance with predictions, all mutations result in major loss of catalytic activity at pH 7.8. However, activity of the Gln88Glu mutant at pH 4.5 exceeded wild-type EcCM. Implications for the mechanism of mutase catalysis are discussed.

The great baseball player Yogi Berra, who is quoted in the title, succinctly described what it meant to learn something that others had long ago appreciated. The mechanism by which the enzyme chorismate mutase accelerates the Claisen rearrangement of chorismic acid has for many years perplexed and intrigued chemists and biochemists. Yet classical effects of solvents and catalysts, which were largely ignored by the chemical community, not only provided important clues about the mechanism of the enzyme, but put the Claisen rearrangement in a new perspective. Whereas chorismic acid once seemed exceptional because it rearranged so rapidly under physiological conditions, it is now clear that even allyl vinyl ether rearranges at room temperature in aqueous solution. While the ability of the enzyme to accelerate the rearrangement of chorismate by a factor of 106 was once considered extraordinary, catalysis by trivalent aluminum compounds matches, and in some cases exceeds, those rate enhancements. Therefore, it really should not be surprising to learn that Nature has independently evolved several structurally distinct solutions to the design of enzyme catalysts for the rearrangement of chorismic acid.

“Deja-vu all over again”. So beschrieb der beruhmte Baseballspieler Yogi Berra kurz und knapp die Erfahrung, etwas zu lernen, das andere lange vorher begriffen haben. Der Mechanismus, nach dem das Enzym Chorismat-Mutase die Claisen-Umlagerung von Chorisminsaure beschleunigt, hat Chemiker und Biochemiker viele Jahre verblufft und gefesselt. Klassische Losungsmittel- und Katalysatoreffekte, die jedoch von der chemischen Fachwelt zum grosten Teil ignoriert wurden, lieferten nicht nur wichtige Anhaltspunkte hinsichtlich des Mechanismus der enzymkatalysierten Reaktion, sondern stellten die Claisen-Umlagerung in ein neues Licht. Fruher schien Chorisminsaure eine Ausnahme zu sein, da sie sich so schnell unter physiologischen Bedingungen umlagerte. Inzwischen ist klar, das sich sogar Allylvinylether bei Raumtemperatur in wasriger Losung umlagert. Die Fahigkeit des Enzyms, die Umlagerung von Chorismat-Ionen um den Faktor 106 zu beschleunigen, wurde damals als ausergewohnlich angesehen. Die Katalyse mit trivalenten Aluminiumverbindungen erreicht jedoch ebenfalls diese Geschwindigkeitserhohungen und ubertrifft sie in einigen Fallen sogar. Es sollte deshalb wirklich nicht uberraschen, das es in der Natur mehrere strukturell verschiedene Losungen zum Aufbau von Enzymkatalysatoren fur die Umlagerung von Chorisminsaure gibt.

Using cyclic bromonium ion formation as a model, transition state structures were computed using PM3 semi-empirical calculations for syn and anti-electrophilic additions of HOBr to allylically and homoallylically functionalized cyclopentenes.

The transition state for hydrolysis of the N-ribosidic bond of inosine by nucleoside hydrolase has oxocarbenium character and a protonated leaving group hypoxanthine with an sp2-hybridized C1' of the ribosyl [Horenstein, B. A., Parkin, D. W., Estupinan, B.,Schramm, V. L. (1991) Biochemistry 30, 10788-10795]. These features are incorporated into N-(p-nitrophenyl)-D-riboamidrazone, a transition state analogue which binds with a dissociation constant of 2 nM [Boutellier, M., Horenstein, B. A., Semenyaka, A., Schramm, V. L.,Ganem, B. (1994) Biochemistry 33, 3994-4000]. Resonance Raman and ultraviolet-visible absorbance spectroscopy has established that the inhibitor binds as the neutral, zwitterionic species. The enzyme stabilizes a specific resonance state characterized by the quinonoid form of the p-nitrophenyl group with evidence for ion pairing at the nitro group. Incorporation of 15N into a specific position of the amidrazone reveals that the exo-ribosyl nitrogen bonded to the C1' position carries the proton while that bonded to the p-nitrophenyl carbon is unprotonated. This tautomer carries a distributed positive charge centered at the position analogous to C1' of the ribosyl group at the transition state. The molecular electrostatic potentials for the substrate inosine, the transition state, and the transition state inhibitor are compared at the van der Waals surface of the molecules. The tautomer of the inhibitor bound to the enzyme bears a striking electrostatic resemblance to the transition state determined by kinetic isotope effect analysis. The spectral and resonance Raman properties of free and enzyme-bound inhibitor have permitted tautomeric assignment of these species and establish that the enzyme substantially changes the electronic distribution of the bound inhibitor toward that of the enzyme-stabilized transition state.

There are two classes of synergism in cellulase mixtures: synergism between endocellulases and exocellulases, and synergism between certain exocellulases. Exocellulases have been defined traditionally as releasing cellobiose from the nonreducing ends of cellulose, but this definition is inadequate to explain exo/exo synergism. Several recent reports indicate that some exocellulases are capable of hydrolyzing cellulose from the reducing end. The existence of two exocellulase classes with different specificities could provide an explanation for exo/exo synergism. In this paper, we report the substrate specificity of three Thermomonospora fusca (E3, E4, and E6) and two Trichoderma reesei (CBH I and CBH II) exocellulases on labeled cellooligosaccharides. We describe a new nonradioactive technique for determining substrate specificity, in which ion-spray mass spectrometry was used to analyze the products of enzymatic digests of cellopentaose labeled with 18O at the reducing end. Exocellulase reactivity was also investigated on cellopentaose labeled at the nonreducing end with 14C, and cellooligosaccharides reduced with NaBH4. The distribution of label in the reaction products supports the existence of two functional classes of exocellulases. One class (containing CBH I, E4, and E6) preferentially cleaves cellooligosaccharides from the reducing end, while the other (containing E3 and CBH II) preferentially cleaves from the nonreducing end. This classification of exocellulases is consistent with exo/exo synergism experiments, and with published cellulase crystallographic data.

A heterocycloaddition route to complex, naturally-occurring aminocyclopentitols and other 1,2,3,4,5-pentasubstituted cyclopentanes is described based on the photooxygenation of a substituted fulvene.

A short, convergent synthesis of the title compound, (±)-N 1 -(3-aminopropyl)-1,4-diamino-2-butanol 6 , was accomplished in 42% overall yield by means of a highly regioselective 1,3-dipolar nitrone cycloaddition.

The naturally occurring purine and pyrimidine heterocycles found in nucleic acids differ significantly in their basicity. To investigate whether such differences may provide useful mass spectrometric information about nucleic acid sequence and/or composition, the distribution of charge states in a series of oligodeoxynucleotide gas-phase ions was studied by ion spray mass spectrometry (MS). Hexadeoxynucleotides of adenosine, cytidine, guanosine and thymidine were evaluated over the pH range 2.6–7.0 using negative-ion MS. A significant reduction in the maximum charge state was noted for d(pA)6, d(pC)6 and d(G)6 at low pH, while the maximum charge state observed for d(pT)6 was independent of pH. These effects displayed a good correlation with the pKa values of the respective nucleoside bases. The findings suggest that charge-state reduction probably resulted from internal charge neutrazation by gas-phase protonation of the nucleoside base.

Non-covalent binding of antibiotics to their target ligands represents a form of molecular recognition which is of considerable contemporary interest in bioorganic and bioanalytical chemistry. The vancomycin antibiotics, including vancomycin and ristocetin, are a family of complex glycopeptides which bind specifically to the C-terminal sequence X-D-Ala-D-Ala, where × is L-lysine, L-diaminopimelic acid, L-alanine or L-homoserine. It is shown that non-covalent complexation of vancomycin and ristocetin with peptide ligands in solution, a key molecular recognition phenomenon in antibacterial chemotherapy, can be detected and analyzed in the gas phase by ionspray mass spectrometry. Using Nα,Nϵ-diacetyl-L-Lys-D-Ala-D-Ala (Ac2KAA) as a representative ligand, it is further demonstrated that correlations of relative ion abundance with ligand concentrations in solution afford a direct method for measuring the binding constants of vancomycin and ristocetin complexes with target peptide sequences in bacterial cell wall. Results for ristocetin-Ac2KAA (Ka = 6.25 × 105 l mol−1) and vancomycin-Ac2KAA (Ka = 7.33 × 105 l mol−1, are in reasonable agreement with previously values [Ka = 5.9 × 105] and 1.5 × 106 l mol−1, respectively).

Chorismate mutase catalyzes the rearrangement of chorismic acid to prephenic acid, which is the first committed step in the biosynthesis of aromatic amino acids. Its catalytic mechanism has been much studied, but is poorly understood. Recent structural information on enzymes from two species, and on an antibody that catalyzes the same reaction, has shed new light on this topic.

Analogs and homologs of PDMP were synthesized, based on its structure (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol). This compound had previously been found to block the synthesis of GlcCer (glucosylceramide). Increasing the acyl chain length from 10 to 16 carbon atoms greatly enhanced the efficacy of the enzyme inhibitor, as did the use of a less polar cyclic amine, especially a pyrrolidine instead of a morpholine ring. Replacement of the phenyl ring by a chain corresponding to sphingosine also yielded a strongly inhibitory material. By using a chiral synthetic route, we showed that the isomers active against GlcCer synthase had the R,R-(D-threo)-configuration. However, strong inhibition of the growth of human cancer cells in plastico was produced by both the threo and erythro racemic compounds, showing involvement of an additional factor (beyond simple depletion of cell glycosphingolipids by blockage of GlcCer synthesis). The growth arresting effects could be correlated with increases in cellular ceramide and diglyceride levels. The aliphatic pyrrolidino compound was strongly inhibitory toward the glucosyltransferase and produced almost complete depletion of glycolipids, but did not inhibit growth or cause an accumulation of ceramide. Attempts were made to see whether the differences in growth effects could be attributed to the influence of the inhibitors on related enzymes (ceramide and sphingomyelin synthase and ceramidase and sphingomyelinase). While some stimulation of enzyme activity was noted, particularly at high inhibitor concentrations (50 microM), these findings did not explain the differing effects of the different inhibitors. The best inhibitors of GlcCer synthase compared favorably in efficacy with some cancer chemotherapeutic drugs in current use when tested with a battery of human cancer cells.

The well known biospecific noncovalent receptor-ligand association complexes between the immunophilin FKBP and the immunosuppressive drugs FK506 and Rapamycin (RM) were investigated by on-line capillary electrophoresis-mass spectrometry (CE-MS) under selected ion monitoring (SIM) conditions and by CE-MS with tandem mass spectrometry (CE-MS/MS) under selected reaction monitoring (SRM) conditions. Solutions of hFKBP (33.3 µM) were dissolved in 50 mM ammonium acetate at pH 7.5. Samples that contained 100 µM of FK506 or RM also were prepared under the same solution conditions. By using these aqueous pH neutral conditions, samples were analyzed by SIM CE-MS and SRM CE-MS and the target complexes were separated by CE with mass spectrometer detection of the individual complexes between FKBP and FK506 [hFKBP + FK506 + 7HJ(7+) as well as FKBP and RM [hFKBP + RM + 7HJ(7+). In an experiment where a mixture of FK506 and RM was analyzed in the presence of FKBP, a nine-to-one ratio of ion current abundances between the RM and FK506 complexes was observed as reported in the literature from other studies. These results suggest that CE-MS and CE-MS/MS may be yet another analytical method for studying noncovalent interactions of biologically important macromolecules under physiological conditions.

Two examples in nature of enzyme-catalyzed hydrolysis of cyclohexenylamines to cyclohexenols have no known counterpart in the literature of organic chemistry. Conditions which lead to the observed equilibrium are discussed.

Asymmetric syntheses of guanidine 3 and N-aminoguanidine 4 are described from (−)-epoxy alcohol 5 . Compounds 3 and 4 , which resemble D-glucose and D-mannose, were designed as generic hexopyranose substitutes and represent new templates for assembling glycomimetic structures.

Condensation of unsubstituted isocyanoacetamides with aldehydes and ketones, or their derived iminium ions, leads to 2-substituted-5-aminooxazoles, which are useful compounds for drug discovery programs.

The simple protocol allows a selective dichlorination at the nitrile carbon independent of the substitution pattern.

The reaction of aliphatic and aromatic isonitriles with sulfuryl chloride provides an efficient, general route to the corresponding dichlorides without byproducts of free-radical substitution.

Ethyl 2-isocyanoacetate Ethyl 2-isocyantoacetate Keywords: Isocyanates; Isonitriles; Dimethyl sulfide; DMSO; Trifluoroacetic anhydride; Catalyst; Diisocyanates; Waste disposal; Safety

A convergent synthesis of the aminocyclitol allosamizoline 1 , which is found in a class of pseudotrisaccharide chitinase inhibitors known as the allosamidins, is reported.