Nicole Jung

New Catalysts for the Transition-Metal-Catalyzed Synthesis of Aziridines

Aziridines are especially in demand because of their natural occurrence in diverse biologically active compounds and their manifold transformations in chemical reactions. The ring constraint renders them very reactive substances. In the presence of nucleophiles (N, O, S, C nucleophiles, and halides) they undergo ring-opening, they are used for [3+2] cycloadditions and [3+3] annulations, and they undergo ring extension in reactions with isocyanates and nitriles. Furthermore, aziridines can undergo rearrangements or they can be allylated, alkylated, or arylated through palladium catalysis, to mention only a few possible reactions. Traditionally, aziridines are synthesized by the cyclization of amino alcohols (Wenker synthesis), and by the reaction of imines with diazo-containing compounds (aza-Darzens reaction) or sulfur ylides (Corey–Chaykovsky aziridination). 5] As an alternative to these protocols more and more procedures have been presented over the past years for the (C2 + N1) synthesis of aziridines through the reaction of alkenes with nitrenes (or their precursors). The possible variations of this nitrogen-transfer reaction differ in the choice of the nitrene source and the catalyst. The transformation of alkenes with phenyl imino iodinanes as the nitrogen-transfer reagents under manganese and iron catalysis (Mn and Fe porphyrins) has been known for roughly 30 years and gives—depending on the catalyst—modest to very good yields. Fundamental progress has been achieved through the use of copper catalysts by Evans et al. and rhodium catalysts by M ller et al. Beyond the imino iodinanes, halogen amines (more seldom) and sulfonyl azides or aryl azides can be used as the nitrogen source. Through the appropriate choice of the catalytic system, the 1,3-dipolar cycloaddition of azides can be suppressed and aziridines can be obtained in good to excellent yields according to Scheme 1. The use of azides instead of the often chosen imino iodinanes as the nitrene source has several advantages, especially because application of the latter is limited owing to the more laborious preparation, the formation of side products, and poor solubility. One disadvantage of using azides is that their activation often requires high temperatures or irradiation. To facilitate the elimination of nitrogen and the transfer of the nitrene under mild conditions, different catalysts for azide-mediated aziridine syntheses on the basis of iron, cobalt, manganese, copper, and ruthenium have been developed. 5a, 6a] Of these, outstanding Co and Cu catalysts (Scheme 2) have been used successfully to develop asymmetric syntheses of aziridines with good to excellent enantioselectivities. The hitherto known procedures can be applied to a broad spectrum of alkenes and—although the mechanism and the structure of the active species are not fully understood— excellent selectivities and yields of the desired aziridines have been achieved with a variety of studied catalysts. While the transition-metal-catalyzed syntheses of aziridines via sulfonyl azides (and their derivatives) as the N1 sources are universally applied in many fields, transformations of aryl azides have not been frequently described despite their many advantages. The azides, which are used as starting materials, can be synthesized very easily and inexpensively and they allow for a wide diversity of substrates. Through the direct introduction of the desired aryl residue (in comparison to sulfonyl azides) the more complex two-step variant of removal of the sulfonyl residue and introduction of necessary substituents can be circumvented. This advantage is of special interest when one considers the low stability of tosyl aziridines and the Scheme 1. Variations of the transition-metal-catalyzed synthesis of aziridines.

Azides – Diazonium Ions – Triazenes: Versatile Nitrogen-rich Functional Groups

For more than 100 years, nitrogen-rich compounds such as azides, diazonium ions, and triazenes have proved to be extremely valuable. Because these functional groups can be easily introduced into various substrates, they are frequently used nowadays. More importantly, they can be converted into a great number of other functional groups. The scope of this article is thus to summarize possible synthetic routes for the formation of these functional groups as well as to highlight some of the most prominent applications of these exciting moieties in chemical biology and combinatorial chemistry. Many of the most famous name reactions such as the Staudinger reduction, Staudinger ligation, Sandmeyer reaction, Wallach reaction, Mitsunobu reaction, Huisgen reaction, Balz–Schiemann reaction, Meerwein arylation, Pschorr reaction or Gomberg–Bachmann reaction are covered.

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif

Background: The interaction surface of coactivators and the androgen receptor (AR) is an important target for prostate cancer therapeutics. Results: A new interface formed by binding of the sequence (GARRPR) and the allosteric pocket (BF-3) of the AR has been identified. Conclusion: GARRPR binding modulates AR activity. Significance: The GARRPR/BF-3 interaction is a novel regulatory hub for AR activity. The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.

Diaryl Ether and Diaryl Thioether Syntheses on Solid Supports via Copper (I)-Mediated Coupling

An efficient method to synthesize diaryl ethers and thioethers on solid supports is described. Starting from immobilized phenols or arylhalides, coupling with an access of aryliodides/arylbromides or phenolic/thiophenolic substrates in solution was successful in the presence of CuCl and Cs(2)CO(3) as base. Coupling conditions known from solution-phase syntheses of diaryl ethers have been effectively modified and adapted to solid-phase synthesis. Optimized conditions enabled the coupling of sterically hindered and/or electronically deactivated aryl moieties. After coupling, a newly developed diversity-generating linker based on cinnamic acid allowed the diaryl ethers to be cleaved from the resin either via saponification/transesterification or via ozonolysis. Latter offers the possibility of generating several additional compounds by simple variation of the cleavage conditions. The target substances were generally isolated in good to excellent yields and high purities.

Multifunctional Linkers for Combinatorial Solid Phase Synthesis

This review covers recent results in the area of multifunctional linkers for solid phase synthesis during the period 2000–2006.

Reactions of resin-bound triazenes with dithianylium tetrafluoroborates: efficient synthesis of α-azo ketene dithioacetals and related hydrazones.

The conversion of dithianylium cations into α-azo ketene dithioacetals via addition of polymer-bound diazonium precursors is shown. This new procedure allows the synthesis of α-azo ketene dithioacetals in one step within 2-90 min at rt and yields highly pure compounds that do not have to be purified in most cases. The α-azo ketene dithioacetals obtained have been shown to be valuable intermediates for the synthesis of hydrazones, α-halogenated α-azo ketene dithioacetals, and azo-functionalized dienes.

Solid Phase Synthesis of (Benzannelated) Six-Membered Heterocycles via Cyclative Cleavage of Resin-Bound Pseudo-Oxazolones

A solid supported procedure for the synthesis of benzoxazinones, dihydropyrazinones, quinoxalinones, and dihydrooxazinones using immobilized oxazolones in combination with difunctional nucleophiles as cleavage agent is presented. The scope of the novel method has been demonstrated through subsequent modification of the parent oxazolone scaffold on solid supports using conversions with electrophiles or CuAAC reactions to give functionalized pyrazin-2-ones. The described method allows the synthesis of the target heterocycles in good yields via three to five steps on solid phases with only one chromatographic purification step.

A Chemical Screening Procedure for Glucocorticoid Signaling with a Zebrafish Larva Luciferase Reporter System

Glucocorticoid stress hormones and their artificial derivatives are widely used drugs to treat inflammation, but long-term treatment with glucocorticoids can lead to severe side effects. Test systems are needed to search for novel compounds influencing glucocorticoid signaling in vivo or to determine unwanted effects of compounds on the glucocorticoid signaling pathway. We have established a transgenic zebrafish assay which allows the measurement of glucocorticoid signaling activity in vivo and in real-time, the GRIZLY assay (Glucocorticoid Responsive In vivo Zebrafish Luciferase activitY). The luciferase-based assay detects effects on glucocorticoid signaling with high sensitivity and specificity, including effects by compounds that require metabolization or affect endogenous glucocorticoid production. We present here a detailed protocol for conducting chemical screens with this assay. We describe data acquisition, normalization, and analysis, placing a focus on quality control and data visualization. The assay provides a simple, time-resolved, and quantitative readout. It can be operated as a stand-alone platform, but is also easily integrated into high-throughput screening workflows. It furthermore allows for many applications beyond chemical screening, such as environmental monitoring of endocrine disruptors or stress research.

Delphinidin is a novel inhibitor of lymphangiogenesis but promotes mammary tumor growth and metastasis formation in syngeneic experimental rats

We have recently demonstrated that the anthocyanidin delphinidin (DEL), one of the most abundant dietary flavonoids, inhibits activation of ErbB and vascular endothelial growth factor receptor family members. These receptors play crucial roles in the context of tumor progression and the outgrowth of blood and lymphatic vessels. Here, we have developed an improved chemical synthesis for DEL in order to study the effects of the aglycon and its degradation product gallic acid (GA) on endothelial and tumor cells in vitro and in vivo. We found that DEL blocked the proliferation in vitro of primary human blood and lymphatic endothelial cells as well as human HT29 colon and rat MT-450 mammary carcinoma cells in a dose-dependent manner. In contrast, its degradation product GA had little effect. At higher concentrations, DEL induced apoptosis of endothelial and tumor cells. Furthermore, DEL potently blocked the outgrowth of lymphatic capillaries in ex vivo lymphangiogenesis assays. In the MT-450 rat syngeneic breast tumor model, it also significantly reduced angiogenesis and tumor-induced lymphangiogenesis when administered in vivo. These data reveal DEL to be a novel antilymphangiogenesis reagent. Surprisingly, however, the application of DEL unexpectedly promoted tumor growth and metastasis in the MT-450 tumor model, suggesting that the antiproliferative effect of DEL on cultured cells does not necessarily reflect the response of tumors to this anthocyanidin in vivo. Furthermore, while DEL may have utility as a cancer chemopreventative agent, its ability to promote tumor growth once a neoplasm develops also needs to be taken into consideration.

Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer

Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.