We describe herein the design and synthesis of a new class of dialkylarylphosphine ligands incorporating a Lewis-basic urea subunit. The ligand synthesis consisted of six linear steps and was enabled by the discovery of a new N-to-N alkyl migration reaction. This new series of dialkylarylphosphine urea ligands were applied in common palladium-catalyzed cross-coupling reactions for the formation of carbon-carbon and carbon-nitrogen bonds in moderate to high yields.

The enediyne antitumor antibiotics have remarkable structures and exhibit potent DNA cleavage properties that have inspired continued interest as cancer therapeutics. Their complex structures and high reactivity, however, pose formidable challenges to their production and development in the clinic. We report here proof-of-concept studies using a mutasynthesis strategy to combine chemical synthesis of select modifications to a key iodoanthracene-γ-thiolactone intermediate in the biosynthesis of dynemicin A and all other known anthraquinone-fused enediynes (AFEs). By chemical complementation of a mutant bacterial producer that is incapable of synthesizing this essential building block, we show that derivatives of dynemicin can be prepared substituted in the A-ring of the anthraquinone motif. In the absence of competition from native production of this intermediate, the most efficient utilization of these externally-supplied structural analogues for precursor-directed biosynthesis becomes possible. To achieve this goal, we describe the required Δ blocked mutant and a general synthetic route to a library of iodoanthracene structural variants. Their successful incorporation opens the door to enhancing DNA binding and tuning the bioreductive activation of the modified enediynes for DNA cleavage.

We herein report a protocol for the asymmetric aldol-initiated cascade addition of isoxazolidin-5-ones to -cyanobenzaldehydes by using 's bifunctional organocatalyst. This approach allows for the synthesis of various novel β-amino acid-phthalide conjugates with good enantio- and diastereoselectivities in reasonable yields and the further ring-opening of these compounds to acyclic carboxylic acid derivatives was demonstrated too.

Reactions are described for complexes of the form WTp(NO)(PMe)(η-arene) and various amines, where the arene is benzene or benzene with an electron-withdrawing substituent (CF, SOPh, SOMe). The arene complex is first protonated to form an η-arenium species, which then selectively adds the amine. The resulting η-5-amino-1,3-cyclohexadiene complexes can then be subjected to the same sequence with a second nucleophile to form 3-aminocyclohexene complexes, where up to three stereocenters originate from the arene carbons. Alternatively, 1,3-cyclohexadiene complexes containing an ester group at the 5 position (also prepared from an arene) can be treated with acid followed by an amine to form trisubstituted 3-aminocyclohexenes. When the amine is primary, ring closure can occur to form a -fused bicyclic γ-lactam. Highly functionalized cyclohexenes can be liberated from the tungsten through oxidative decomplexation. The potential utility of this methodology is demonstrated in the synthesis of the alkaloid γ-lycorane. An enantioenriched synthesis of a lactam precursor to γ-lycorane is also described. This compound is prepared from an enantioenriched version of the tungsten benzene complex. Regio- and stereochemical assignments for the reported compounds are supported by detailed 2D-NMR analysis and 13 molecular structure determinations (SC-XRD).

The key mRNA-binding proteins HuR and AUF1 are reported stress sensors in mammals. Intrigued by recent reports of sensitivity of these proteins to the electrophilic lipid prostaglandin A2 and other redox signals, we here examined their sensing abilities to a prototypical redox-linked lipid-derived electrophile, 4-hydroxynonenal (HNE). Leveraging our T-REX electrophile delivery platform, we found that only HuR, and not AUF1, is a kinetically-privileged sensor of HNE in HEK293T cells, and sensing functions through a specific cysteine, C13. Cells depleted of HuR, upon treatment with HNE, manifest unique alterations in cell viability and Nrf2-transcription-factor-driven antioxidant response (AR), which our recent work shows is regulated by HuR at the Nrf2-mRNA level. Mutagenesis studies showed that C13-specific sensing alone is not sufficient to explain HuR-dependent stress responsivities, further highlighting a complex context-dependent layer of Nrf2/AR regulation through HuR.

Human 15-lipoxygenase-1 (15-LOX-1) belongs to the class of lipoxygenases, which catalyze oxygenation of polyunsaturated fatty acids, such as arachidonic and linoleic acid. Recent studies have shown that 15-LOX-1 plays an important role in physiological processes linked to several diseases such as airway inflammation disease, coronary artery disease, and several types of cancer such as rectal, colon, breast and prostate cancer. In this study, we aimed to extend the structural diversity of 15-LOX-1 inhibitors, starting from the recently identified indolyl core. In order to find new scaffolds, we employed a combinatorial approach using various aromatic aldehydes and an aliphatic hydrazide tail. This scaffold-hopping study resulted in the identification of the 3-pyridylring as a suitable replacement of the indolyl core with an inhibitory activity in the micromolar range ( =16±6 μm) and a rapid and efficient structure-activity relationship investigation.

The construction of DNA-encoded chemical libraries (DECLs) crucially relies on the availability of chemical reactions, which are DNA-compatible and which exhibit high conversion rates for a large number of diverse substrates. In this work, we present our optimization and validation procedures for three copper and palladium-catalyzed reactions (Suzuki cross-coupling, Sonogashira cross-coupling and copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC)), which have been successfully used by our group for the construction of large encoded libraries.

Oligo-arginines are thoroughly studied cell-penetrating peptides (CPPs, Figures 1 and 2). Previous investigations with the octaarginine salt of the phosphonate fosmidomycin (herbicide and anti-malaria drug) have shown a 40-fold parasitaemia inhibition with , compared to fosmidomycin alone (Figure 3). We have now tested this salt, as well as the corresponding phosphinate salt of the herbicide glufosinate, for herbicidal activity with whole plants by spray application, hoping for increased activities, decreased doses. However, both salts showed low herbicidal activity, indicating poor foliar uptake (Table 1). Another pronounced difference between and activity was demonstrated with various cell-penetrating octaarginine salts of fosmidomycin: intravenous injection to mice caused of the animals within minutes, even at doses as low as 1.4 μmol/kg (Table 2). The results show that use of CPPs for drug delivery, for instance to cancer cells and tissues, must be considered with due care. The biopolymer cyanophycin is a poly-aspartic acid containing argininylated side chains (Figure 4); its building block is the dipeptide H-Asp-Arg-OH (H-Adp-OH). To test and compare the biological properties with those of octaarginines we synthesized Adp-derivatives (Figure 5). Intravenouse injection of H-Adp-NH into the tail vein of mice with doses as high as 45 μmol/kg causes no symptoms whatsoever (Table 3), but H-Adp-NH is not cell penetrating (HEK293 and MCF-7 cells, Figure 6). On the other hand, the fluorescently labeled octamers FAM-(Adp(OMe))-NH and FAM-(Adp(NMe))-NH with ester and amide groups in the side chains exhibit mediocre to high cell-wall permeability (Figure 6), and are toxic (Table 3). Possible reasons for this behavior are discussed (Figure 7) and corresponding NMR spectra are presented (Figure 8).

Mixed self-assembly of ligands and , PXDA (), and Pd(NO) afforded metal organic polyhedra ( - ) which bear 24 covalently attached CB[7] and cyclooctyne moieties. Post assembly modification (PAM) of by covalent strain promoted alkyne azide click reaction provided bearing covalently attached functionality (PEG, sulfonate, biotin, c-RGD, fluorescein and cyanine). Orthogonal CB[7] guest mediated non-covalent PAM of with afforded and . Flow cytometry analysis of the uptake of toward U87 cells demonstrated improved uptake relative to control MOP lacking c-RGD ligands. These results suggest a broad applicability of orthogonally functionalizable (covalent and non-covalent) MOPs in targeted drug delivery and imaging applications.

The full details of mechanistic investigation on enantioselective sulfenofunctionalization of alkenes under Lewis base catalysis are described. Solution spectroscopic identification of the catalytically active sulfenylating agent has been accomplished along with the spectroscopic identification of putative thiiranium ion intermediates generated in the enantiodetermining step. The structural insights gleaned from these studies informed the design of new catalyst architectures to improve enantioselectivity. In addition, structural modification of the sulfenylating agents had a significant and salutary effect on the enantioselectivity of sulfenofunctionalization which was demonstrated to be general for trans disubstituted alkenes. Whereas electronic modulation had little effect on the rate and selectivity, steric bulk on arylsulfenylphthalimides was very beneficial.

3D-Printing with the well-established 'Fused Deposition Modeling' technology was used to print totally gas-tight reaction vessels, combined with printed cuvettes, inside the inert-gas atmosphere of a glovebox. During pauses of the print, the reaction flasks out of acrylonitrile butadiene styrene were filled with various reactants. After the basic test reactions to proof the oxygen tightness and investigations of the influence of printing within an inert-gas atmosphere, scope and limitations of the method are presented by syntheses of new compounds with highly reactive reagents, such as trimethylaluminium, and reaction monitoring UV/VIS, IR, and NMR spectroscopy. The applicable temperature range, the choice of solvents, the reaction times, and the analytical methods have been investigated in detail. A set of reaction flasks is presented, which allow routine inert-gas syntheses and combined spectroscopy without modifications of the glovebox, the 3D-printer, or the spectrometers. Overall, this demonstrates the potential of 3D-printed reaction cuvettes to become a complementary standard method in inert-gas chemistry.

Four new phenolic derivatives, including two phenylpropanoid glycosides, one benzoate glycoside, and one lignan glycoside, together with one known glyceride, were isolated from the root bark of . The structures of the new compounds were elucidated as 3-{4-[(6--acetyl--D-glucopyranosyl) oxy]-3,5-dimethoxyphenylpropanoic acid (), (+)-[5,6,7,8-tetrahydro-7- (hydroxylmethyl)-10,11-dimehoxydibenzo[,][8]annulen-6-yl]methyl -D-glucopyranoside (), (+)-methyl 4-[6--{3-hydroxy-3-methyl-5-(1-methylpropyl)oxy]-5-oxopentanoyl}-4--(-D-glucopyranosyl)--D-glucopyranosyl)oxy]-3-methoxybenzoate (), and 2-methoxy-4-[(1)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl 6--{3-hydroxy-3-methyl-5-[(1-methylpropyl)oxy]-5-oxopentanoyl-4---D-glucopyranosyl--D-glucopyranoside () on the basis of spectroscopic techniques including NMR and MS analyses. The known compound was identified as glycer-2-yl ferulate () by comparing its physical and spectral data with those reported in the literature.

The origin of the variation in the regioselectivity of the nucleophilic ring-opening of a series of bicyclic aziridinium ions derived from -alkylprolinols was investigated by quantum chemical computations (M06-2X/6-31+G(d,p)-SMD). These aziridiniums differ only in the degree and the stereochemistry of fluoro substitution at C(4). With the azide ion as nucleophile, the ratio of the piperidine to the pyrrolidine product was computed. An electrostatic effect influences the conformation of the adjoining five-membered ring in the fluorinated bicyclic aziridinium. This controls the regioselectivity of the aziridinium ring-opening.

Two new natural compounds, (1,2)-2-(6-hydroxyhexylidene)cyclopropyl--D-glucopyranoside () and (6)-6-[(2)-2-(-D-glucopyranosyloxy)cyclopropylidene]hexanoic acid (), glucosides of a very rare methylidenecyclopropane alcohol, as well as two known glycosides of phenolic acids, namely 4---D-glucopyranosylcaffeic acid () and ()-4---D-glucopyranosylcoumaric acid (), and methyl -fructofuranoside () were isolated for the first time from the rhizomes of the tree fern C.Presl. The structures were elucidated on the basis of detailed spectroscopic data analysis, and the structure of 1 was additionally confirmed by X-ray crystal-structure analysis.

The Diels - Alder reaction was applied to 4,5-epoxymorphinan opioids to generate a novel aromatic cycloadduct at C(7) - C(8): Thermolytic cleavage of sultine 8 produced the reactive diene o-quinodimethane 7 which condensed favorably with codeine (11), but not with codeinone (9) or 14- hydroxycodeinone (10), producing the desired tetrahydronaphtho adduct 12 with (7R,8R) geometry (Scheme). The configuration of the cycloadduct was determined by 1D- and 2D-NMR experiments. The unanticipated reactivity of these codeine derivatives was investigated by quantum-mechanical calculations, and it was determined that steric effects of the 6-keto and 14-hydroxy group likely precluded condensation by raising the molecular energy of their respective transition states.

Three new -tetralone galloylglucosides (-), were isolated from the fresh pericarps of (Juglandaceae), together with the six known ones. The structures of the new compounds were determined as 4,6-dihydroxy-α-tetralone-4--[6'--(3″, 4″,5″-trihydroxybenzoyl)]-β-D-glucopyranoside (), (4)-4,5-dihydroxy-α-tetralone-4--[6'--(3″,4″,5″-trihydroxybenzoyl)]-β-D-glucopyranoside () and (4)-4,5,6-tri-hydroxy-α-tetralone-4--[6'--(3″,4″,5″-trihydroxybenzoyl)]-β-D-glucopyranoside (), respectively, on the basis of detailed spectroscopic analyses, and acidic and enzymatic hydrolysis. The antimicrobial activities of the isolated compounds (, and -) were evaluated.

The synthesis of the cyclen derivative H(4)L(1)·2 HBr containing four 2-hydroxybenzamide groups is described. The spectroscopic properties of the Ln(III) conplexes of L(1) (Ln=Gd, Tb, Yb, and Eu) reveal changes of the UV/VIS-absorption, circular-dichroism-absorption, luminescence, and circularly polarized luminescence spectra. It is shown that at least two metal-complex species are present in solution, whose relative amounts are pH dependent. At pH > 8.0, an intense long-lived emission is observed (for [TbL(1)] and [YbL(1)]), while at pH < 8.0, a weaker, shorter-lived species predominates. Unconventional Ln(III) emitters (Pr, Nd, Sm, Dy, and Tm) were sensitized in basic solution, both in the VIS and in the near-IR, to measure the emission of these ions.

We describe the preparation and fluorescence properties of a set of new nucleosides in which a known hydrocarbon or oligothiophene fluorophore replaces the DNA base at C(1) of the deoxyribose moiety (see 3a - f). These compounds are potentially useful as probes in the study of the structure and dynamics of nucleic acids and their complexes with proteins. In addition, they may find use as fluorescent labels for nucleic-acid-based biomedical diagnostics methods. The fluorophores conjugated to deoxyribose at C(1) in the α-d-form include terphenyl, stilbene, terthiophene, benzoterthiophene, and pyrene. Also included is a non-fluorescent spacer in which cyclohexene replaces the DNA base. The nucleosides are derived from brominated fluorophore precursors and Hoffer's 2-deoxy-3,5-di-O-(p-toluoyl)-d-ribofuranosyl chloride. The emission maxima of the free nucleosides range from 345 to 536 nm. Also described are the 5'-(dimethoxytrityl) 3'-O-phosphoramidite derivatives 5a - f, suitable for incorporation into oligonucleotides by automated synthesizers.

The template-directed oligomerization of nucleoside-5'-phosphoro-2-methyl imidazolides on standard oligonucleotide templates has been studied extensively. Here, we describe experiments with templates in which inosinic acid (I) is substituted for guanylic acid, or 2,6-diaminopurine nucleotide (D) for adenylic acid. We find that the substitution of I for G in a template is strongly inhibitory and prevents any incorporation of C into internal positions in the oligomeric products of the reaction. The substitution of D for A, on the contrary, leads to increased incorporation of U into the products. We found no evidence for the template-directed facilitation of oligomerization of A or I through A-I base pairing. The significance of these results for prebiotic chemistry is discussed.

The Tetrahymena group I ribozyme was modified by replacing all 99 component uridine residues with 5-bromouridine. This resulted in a 13-fold reduction in catalytic efficiency in the RNA-catalyzed phosphoester-transfer reaction compared to the behavior of the unmodified ribozyme. A population of 10(13) variant ribozymes was constructed, each containing 5-bromouridine in place of uridine. Five successive 'generations' of in vitro evolution were carried out, selecting for improved phosphoester transferase activity. The evolved molecules exhibited a 27-fold increase in catalytic efficiency compared to the wild-type bromouridine-containing ribozyme, even exceeding that of the wild-type ribozyme in the non-brominated form. Three specific mutations were found to be responsible for this altered behavior. These mutations enhanced activity in the context of 5-bromouridine, but were detrimental in the context of unmodified uridine. The evolved RNAs not only tolerated but came to exploit the presence of the nucleotide analogue in carrying out their catalytic function.

Environmental conditions play an important role in conceptual studies of prebiotically relevant chemical reactions that could have led to functional biomolecules. The necessary source compounds are likely to have been present in dilute solution, raising the question of how to achieve selective concentration and to reach activation. With the assumption of an initial 'RNA World', the questions of production, concentration, and interaction of aldehydes and aldehyde phosphates, potential precursors of sugar phosphates, come into the foreground. As a possible concentration process for simple, uncharged aldehydes, we investigated their adduct formation with sulfite ion bound in the interlayer of positively charged expanding-sheet-structure double-layer hydroxide minerals. Minerals of this type, initially with chloride as interlayer counter anion, have previously been shown to induce concentration and subsequent aldolization of aldehyde phosphates to form tetrose, pentose, and hexose phosphates. The reversible uptake of the simple aldehydes formaldehyde, glycolaldehyde, and glyceraldehyde by adduct formation with the immobilized sulfite ions is characterized by equilibrium constants of K=1.5, 9, and 11, respectively. This translates into an observable uptake at concentrations exceeding 50 mM.