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Supplementary Figure 2 from Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

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Supplementary Figure 5 from Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Supplementary Figure 1 from Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Supplementary Figure Legends 1-5 from Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Supplementary Figure 4 from Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

We present alkali salts of amino acids as functional, non-toxic, non-hazardous, non-volatile, chemically stable, and cheap alkaline additives for common acidic corrosion inhibitors. The resulting mixtures have been evaluated for Co, Ni, and Cu leaching and were analyzed by chip filter assay, potentiodynamic polarization measurements, electrochemical impedance measurements, and gravimetry for corrosion protection of iron and steel in aqueous environment at slightly alkaline pH. Leaching of Co and Ni was found to depend on the corresponding complex stabilities. Taurine (Tau) as well as aminohexanoic acid (AHX) leads to low leaching of Co and Ni. Particularly AHX is an attractive low leaching additive leading to lower Co and Ni concentrations in solution than currently used amino alcohols. Glu and Tau were found to synergistically interact with several acidic corrosion inhibitors of the carboxylic acid and the phosphonic acid type. Tau had a particularly positive impact on the protective properties of carboxyphosphonic acids. Glu had also a positive effect on the anti-corrosive properties of several acidic corrosion inhibitors and served as an anti-scalant. Alkali salts of Glu and Tau might thus serve as commercially and ecologically attractive substitutes for current alkaline additives to acidic corrosion inhibitors.

The development of novel prostate-specific membrane antigen (PSMA)-targeted radioactive theranostic agents is currently limited to facilities capable of working with high-energy radioisotopes. Even preselection of lead structures in vitro relies mostly on radioactive assays with PSMA(+) LNCaP and PSMA(-) PC-3 cells. Assays utilizing radioisotopes are time consuming, costly, and limit discovery to a small group of scientists with special facilities. Nonradioactive alternatives are therefore needed in the field. In this paper, we describe an inductively coupled plasma mass spectrometry (ICP-MS)-based method for the evaluation of PSMA-targeting ligands conjugated to DOTA-chelates of Europium. This method is based on LNCaP and PC-3 cells and has been validated with the well-established targeting ligand PSMA-617.

Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris‐based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization.

International journal of molecular sciences 22(7), 3691 (2021). doi:10.3390/ijms22073691, Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time., Published by Molecular Diversity Preservation International, Basel

Hyperglycemia enhancing the intracellular levels of reactive oxygen species (ROS) contributes to dysfunction and progressive loss of beta cells and thereby to diabetes mellitus. The oxidation sensitive calcium/calmodulin dependent phosphatase calcineurin promotes pancreatic beta cell function and survival whereas the dual leucine zipper kinase (DLK) induces apoptosis. Therefore, it was studied whether calcineurin interferes with DLK action. In a beta cell line similar concentrations of H2O2 decreased calcineurin activity and activated DLK. DLK interacted via its φLxVP motif (aa 362-365) with the interface of the calcineurin subunits A and B. Mutation of the Val prevented this protein protein interaction, hinting at a distinct φLxVP motif. Indeed, mutational analysis revealed an ordered structure of DLK's φLxVP motif whereby Val mediates the interaction with calcineurin and Leu maintains an enzymatically active conformation. Overexpression of DLK wild-type but not the DLK mutant unable to bind calcineurin diminished calcineurin-induced nuclear localisation of the nuclear factor of activated T-cells (NFAT), suggesting that both, DLK and NFAT compete for the substrate binding site of calcineurin. The calcineurin binding-deficient DLK mutant exhibited increased DLK activity measured as phosphorylation of the downstream c-Jun N-terminal kinase, inhibition of CRE-dependent gene transcription and induction of apoptosis. These findings show that calcineurin interacts with DLK; and inhibition of calcineurin increases DLK activity. Hence, this study demonstrates a novel mechanism regulating DLK action. These findings suggest that ROS through inhibition of calcineurin enhance DLK activity and thereby lead to beta cell dysfunction and loss and ultimately diabetes mellitus.

Despite the fact that various enantioselective catalytic reactions are available for many important stereoselective reactions, diastereoselective auxiliary-controlled synthesis is still an important area of organic synthesis. Chiral pyrrolidine auxiliaries are frequently used in this context, due to good availability and efficient transfer of chirality via the rigid pyrrolidine scaffold. The following chapter focusses on recent examples and gives a brief overview of applications of pyrrolidine auxiliaries in diastereoselective syntheses. Illustrative examples were chosen to spotlight the underlying principles.

The edible fungus Pleurotus sapidus (PSA) is a particularly interesting biocatalytic system for allylic oxidation and has a remarkably broad substrate range from terpenoids to fatty acids. The oxidations are most likely catalyzed by a lipoxygenase and involve the formation of peroxides via radical intermediates in the first rate-limiting step. We provide herein a rationalization of the observed regioselectivity of these conversions by means of computational determination of bond dissociation enthalpies of a set of tailor-made spirocyclic terpenoids. It was found that only strongly activated allylic positions (BDH298 of

Herein, we present the synthesis and structural analysis of metal complexes of enantiomerically pure 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazidoethylacetic acid (DOTAZA). DOTAZA is a new tunable analog of DOTA, a clinically approved chelator for various pharmaceutically relevant metal ions. In this work, we investigate the complexation chemistry of DOTAZA and report the crystal structures of a number of complexes with pharmaceutically relevant metal ions such as Gd3+ [magnetic resonance imaging (MRI)], Eu3+ (luminescence spectroscopy), Y3+ [positron emission tomography (PET)], In3+ [single-photon-emission computed tomography (SPECT)], and Na+. These structures provide useful information for imaging applications and demonstrate the potential of DOTAZA to form stable complexes. Owing to its clickable azide functionalities, it may be used for the development of tailored imaging reagents that retain the positive complexation chemistry of the parent compound DOTA.

Polyethylene (PE) foils were modified with potent contact-active antibacterial quaternary ammonium salts (QAS) by an atmospheric air plasma activation step, followed by graft-polymerisation of vinylbenzyltrimethylammonium chloride (VBTAC) monomers. The presented approach uses a cost efficient air plasma activation and subsequent radical polymerisation in highly concentrated aqueous monomer solutions to generate efficient antibacterial materials. The obtained contact-active poly-VBTAC modified PE foils feature a homogeneous and 300 nm thick polymer layer with a high charge density of approximately 1016 N+/cm2. The antibacterial properties were evaluated against Gram-negative (P. aeruginosa, E. coli) and Gram-positive (S. aureus, S. epidermidis) bacteria. The materials showed strong antibacterial activity by eradicating all the inoculated bacteria with bacterial challenges of 104 to 105 CFU/cm2 and good reductions even at maximum challenge (108 CFU/cm2). We have confirmed contact-activity by an agar diffusion assay. The obtained materials are therefore highly attractive for applications, for example, in packaging and are a contribution to an ecomic and green antimicrobial management without release of biocides to the environment.

Zwitterionic thin films containing α-amino phosphonic acid moieties were successfully introduced on silicon surfaces and their antifouling properties were investigated. Initially, the substrates were modified with a hybrid polymer, composed of poly(methylsilsesquioxane) (PMSSQ) and poly(4-vinyl benzaldehyde) (PStCHO). Next, a Kabachnik-Fields post-polymerization modification (sur-KF-PMR) of the functionalized aldehyde surfaces was conducted with different amines and dialkyl phosphonates. After subsequent deprotection reaction of dialkyl phosphonates, the obtained zwitterionic surfaces were characterized by various techniques and we found excellent antifouling properties of the resulting films.

Dialkyl phosphinates are valuable peptide mimics fo r metallopeptidase targets. Despite their large pharmaceutical potential, the synthesis of many pho sphinates remains challenging. An additional drawback for many applications is the high polarity of the phosphinate group. Herein we describe the synthesis of stereoisomerically pure GPI ( 1), a phosphinate with high binding affinity for the cancer specific zinc peptidase PSMA (prostate speci fic membrane antigen). In addition, analogous cyclic phosphinate esters 13 , 16 and 23 are reported that might be useful as less polar li gands for metallo peptidase binding. The key step to these ne w 1,2-oxaphosphorinan-2-ones is an intramolecular cyclization of an intermediate H-phosphinate. The cyclizations work with modest diastereoselectivities of ~2:1 in favor of the trans arrangement of substituents at 2- and 4-position of the 1,2-oxaphosphorinan-2-one scaffolds.

Lectin–carbohydrate interactions are important for many biological processes of high pharmaceutical interest. Multivalent carbohydrate conjugates (glycoclusters) have been frequently used to study and manipulate these interactions. In this report, we present the synthesis of trimeric glucose and mannose conjugates that have been assembled with an AB3 scaffold based on adamantane. Several neoglycoconjugates bearing three carbohydrates have been synthesized with different ethylene glycol spacers between the sugar moieties and the adamantyl core. An additional orthogonal functionality at the remaining adamantane bridgehead position allows the conjugation of these trimeric cluster glycosides to other functional molecules such as fluorescent dyes or a solid support for the construction of glycoarrays. We have evaluated the binding properties of trivalent carbohydrate derivatives to ConA as a model lectin in solution by STD-NMR and on a lectin array by using fluorescent glycoconjugates.

Terpenoid spiroethers are abundant natural flavors with significant impact, particularly in the food industry. We present in this article the synthesis of new derivatives of the well-known flavors theaspirane and vitispirane using a variant of the Prins cyclization starting from α,β-unsaturated or heterocyclic ketones. When aromatic ketones were used as the starting materials for Lewis acid-mediated cyclizations, an alternative pathway involving a domino sequence of Prins cyclization, followed by an intramolecular Friedel-Crafts alkylation, gave benzoannelated oxabicyclo[3.3.1]nonane derivatives. Different reaction pathways may be triggered by the reaction temperature to give with good selectivity either tetrahydropyran derivatives as conventional Prins products or oxabicyclo[3.3.1]nonane derivatives.

Chiral spirocyclic terpenoids are abundant natural flavors with significant impact particularly on the food industry. Chromatographic methods for analytical and preparative separation of these compounds are therefore of high interest to natural product chemists in academia and industry. Gas chromatography on chiral stationary phases is currently the standard method for the separation of volatile terpenoids, limiting the scale to analytical quantities. We report herein high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) protocols for the chiral separation of several racemic spirocyclic terpenoids such as the important flavors theaspirane and vitispirane. A screening of mobile phases and 16 commercially available chiral stationary phases (CSPs) largely based on polysaccharides led to identification of protocols for the separation of all terpenoids tested. SFC methods were found to be particularly useful for the separation of these spirocyclic flavors due to the volatility and low polarity of the compounds. The reported chiral HPLC and SFC protocols are scalable alternatives to gas chromatographic separations of volatile terpenoid flavors.

Allylic oxidations of olefins to enones allow the efficient synthesis of value-added products from simple olefinic precursors like terpenes or terpenoids. Biocatalytic variants have a large potential for industrial applications, particularly in the pharmaceutical and food industry. Herein we report efficient biocatalytic allylic oxidations of spirocyclic terpenoids by a lyophilisate of the edible fungus Pleurotus sapidus. This ‘’mushroom catalysis’’ is operationally simple and allows the conversion of various unsaturated spirocyclic terpenoids. A number of new spirocyclic enones have thus been obtained with good regio- and chemoselectivity and chiral separation protocols for enantiomeric mixtures have been developed. The oxidations follow a radical mechanism and the regioselectivity of the reaction is mainly determined by bond-dissociation energies of the available allylic CH-bonds and steric accessibility of the oxidation site.

Benzoboroxoles are known to bind 1,2-diol motifs in carbohydrates in an aqueous environment. Their binding properties have been shown to be dependent on additional recognition sites such as peptides and the number of binding epitopes. In this paper we describe the synthesis of trimeric benzoboroxoles based on a rigid adamantyl core structure. The conjugates are assembled using copper-catalyzed click reactions of azide scaffolds with alkynyl-functionalized benzoboroxoles. The design of our trimeric benzoboroxoles followed a biomimetic principle and imitates the trimeric structure of some natural carbohydrate binding proteins (lectins). With an assortment of appropriately functionalized (3 + 1) adamantane scaffolds, trimeric benzoboroxoles have been generated which were combined with additional functional molecules such as dyes and peptides. In summary, we report a highly effective synthetic approach to modular trimeric boronolectines for the assembly of carbohydrate sensors.

Allylic oxidations of olefins to enones are C–H functionalizations and are valuable organic transformations that permit the synthesis of value-added products from simple precursors. A variety of stoichiometric and catalytic metal-based methods are available for these conversions. In addition, metal-free and biocatalytic protocols are gaining in importance. This review summarizes the available oxidation methods and compares their regio- and chemoselectivities. 1 Introduction 2 Chromium-Based Oxidation 2.1 Stoichiometric Methods 2.2 Catalytic Methods 2.3 Chromium on Solid Support 3 Regio- and Chemoselectivity of Allylic Oxidations 4 Other Metal-Based Oxidations 4.1 Copper Reagents 4.2 Rhodium Reagents 4.3 Selenium Reagents 4.4 Cobalt Reagents 4.5 Ruthenium Reagents 4.6 Palladium Reagents 4.7 Iron Reagents 4.8 Other Metal Reagents 5 Metal-Free and Biocatalytic Methods 5.1 Metal-Free Methods 5.2 Biocatalytic Methods 6 Conclusion

Due to its rigid cage structure, adamantane has received considerable interest as a scaffold with a defined tetrahedral geometry. In this paper we describe orthogonally functionalized tetrasub­stituted adamantane derivatives. These compounds may be conjugated to other functional molecules by standard techniques such as amide formation or click chemistry and are thus useful (3 + 1) scaffolds for medicinal and material chemistry.

By following a biomimetic design principle, tetravalent scaffolds based on an adamantyl and trisalkylmethyl core structure have been synthesized. These scaffolds have been coupled to three catecholamines, thus resembling the characteristic tripodal recognition motif of many natural metal binders, such as mussel adhesion proteins and siderophores, for example, enterobactin. Besides this tripodal recognition element, our scaffolds provide a fourth position for the conjugation of effector molecules. These effectors can be conjugated through biocompatible conjugation techniques to the scaffold and can be used to tailor the properties of different metal surfaces for a range of applications, for example, in implant engineering. Herein, we describe the synthesis of several tripodal metal binders and their immobilization on TiO(2) surfaces by using a simple dip-coating procedure. Furthermore, we demonstrate the conjugation of our surface binders to the dye eosin Y as an effector molecule by peptide coupling. The resulting surfaces have been analyzed by using ellipsometry, time-of-flight secondary ion mass spectrometry, IR spectroscopy, and contact-angle measurements to confirm the specific loading on TiO(2) films and nanoparticles with our trivalent surface binders. As a proof of concept, we have demonstrated the functionalization of TiO(2) nanoparticles with the eosin Y dye.

We present a review of different methods for the preparationof five- and six-membered cyclic hydrazino α-carboxylic acids- andtheir derivatives. These heterocycles are common building blocksin pharmaceuticals and many natural products. In addition, hydrazinocarboxylic acids have been used as auxiliaries and intermediatesin organic syntheses and selected applications are highlighted inthis summary. For six-membered heterocycles (piperazic acids), theliterature since 1998 is covered as a follow-up to the review byCiufolini and Xi. 1 Introduction 2 Synthesis of Five-Membered-Ring Systems 2.1 [3+2] Cycloadditions 2.2 Cyclization of N-Acyl HydrazoniumIons 2.3 [4+2] Cycloadditions 2.4 Tandem and Multicomponent Syntheses 3 Synthesis of Six-Membered-Ring Systems 3.1 Hetero-Diels-Alder Reactions 3.2 Cyclization via Nucleophilic Displacement 3.3 Intramolecular N-Arylation 3.4 Intramolecular Hydrazone Formation 3.5 Intramolecular Lactam Formation 3.6 Ring-Closing Metathesis 4 Summary

A number of natural products with interesting biological properties are based on a diketopiperazine scaffold. In this context, we have developed a diversity oriented and efficient synthetic strategy to highly functionalized proline-based diketopiperazines. In this paper we describe the stereoselective synthesis of various scaffolds resembling abundant natural product core structures. These scaffolds can be conjugated to a solid phase and are thus platforms for the construction of small compound libraries and the synthesis of natural products with diketopiperazine cores.

Efficient syntheses of rigid C3-symmetric scaffolds based on adamantane are described. The scaffolds are available in multigram quantities and have been designed for conjugation to various natural products such as carbohydrates and peptides. They are thus valuable for the construction of strictly defined molecular architectures with threefoldgeometry for applications in bioorganic chemistry, catalysis or material science. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

As a part of our study of the cancer-specific protease PSMA (prostate-specific membrane antigen) we present a stereoselective synthesis of conformationally constrained glutamate mimetics. Key intermediates are azabicycloalkenes which are synthesized via diastereoselective or enantioselective imino-Diels–Alder protocols. The versatility of the route is demonstrated with the preparation of Asp, Glu and HGlu-mimetics based on proline or pipecolic acid scaffolds. These scaffolds are assembled by an oxidative cleavage of azabicycloalkenes and subsequent conversions of the resulting dialdehydes via chlorite oxidation or Wittig olefination. The resulting cyclic amino acids are obtained as Cbz-protected derivatives or free amines ready for further manipulation at their N-terminus and are useful as building blocks for the assembly of conformationally rigid PSMA ligands.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Zwitterionic thin films containing α-amino phosphonic acid moieties were successfully introduced on silicon surfaces and their antifouling properties were investigated. Initially, the substrates were modified with a hybrid polymer, composed of poly(methylsilsesquioxane) (PMSSQ) and poly(4-vinyl benzaldehyde) (PStCHO). Next, a Kabachnik-Fields post-polymerization modification (sur-KF-PMR) of the functionalized aldehyde surfaces was conducted with different amines and dialkyl phosphonates. After subsequent deprotection reaction of dialkyl phosphonates, the obtained zwitterionic surfaces were characterized by various techniques and we found excellent antifouling properties of the resulting films.

A common approach to generate tailored materials and nanoparticles (NPs) is the formation of molecular monolayers by chemisorption of bifunctional anchor molecules. This approach depends critically on the choice of a suitable anchor group. Recently, bifunctional catecholates, inspired by mussel-adhesive proteins (MAPs) and bacterial siderophores, have received considerable interest as anchor groups for biomedically relevant metal surfaces and nanoparticles. We report here the synthesis of new tripodal catecholates as multivalent anchor molecules for immobilization on metal surfaces and nanoparticles. The tripodal catecholates have been conjugated to various effector molecules such as PEG, a sulfobetaine and an adamantyl group. The potential of these conjugates has been demonstrated with the immobilization of tripodal catecholates on ZnO NPs. The results confirmed a high loading of tripodal PEG-catecholates on the particles and the formation of stable PEG layers in aqueous solution.

We have recently described the synthesis of diazabicyclo[4.X.0]alkanes and their use as ligands for the prostate specific membrane antigene (PSMA). The key step of our synthetic route toward these diazabicycloalkanes is an oxidative cleavage of a bicyclic diol moiety followed by the attack of a nitrogen nucleophile to the resulting intermediate bisaldehyde. We herein describe the mechanism of this ring closure and its stereochemical consequences. In addition, we report a convenient method for trapping intermediate bisaldehydes by Wittig reagents. This trapping allows the synthesis of 3,5-disubstituted proline derivatives, which are shown to be versatile precursors for functionalized diazabicycloalkane dipeptide mimetics.

This review focuses on recent synthetic developments for the stereoselective preparation of aza- and diazabicyclo[X.Y.O]alkane dipeptide mimetics of the general structures 1-3. Different synthetic strategies are compared with respect to stereoselectivity as well as flexibility regarding ring sizes, stereochemistry and introduction of side-chains.