Wolfgang Maison

Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAIL(mim/DR5)) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAIL(mim/DR5)-receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAIL(mim/DR5) peptides exerted a cancer cell-selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAIL(mim/DR5) peptide inhibited tumor growth. Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy.

Production of Multimeric Prostate-Specific Membrane Antigen Small-Molecule Radiotracers Using a Solid-Phase 99mTc Preloading Strategy

Small-molecule ligands specific for prostate-specific membrane antigen (PSMA) have the potential to improve prostate cancer imaging. However, highly charged ligands are difficult to label with 99mTc and to purify. In this study, we present an adamantane-trimerized small molecule that has nanomolar binding to PSMA and also has 12 negative charges. Methods: To convert this molecule into a clinically viable SPECT diagnostic, we have developed a simple, cartridge-based, solid-phase prelabeling strategy that, within 25 min, converts readily available and inexpensive 99mTc-pertechnetate into a chemically pure complex, with a reactive N-hydroxysuccinimide (NHS) ester, in neat organic solvent. This stable intermediate can label any amine-containing small molecule or peptide with 99mTc in 1 step, with high specific activity and without the need for high-performance liquid chromatography (HPLC). Results: Solid-phase conversion of 99mTc-pertechnetate to 99mTc-MAS3-NHS (MAS3 is S-acetylmercaptoacetyltriserine) could be completed in 25 min, with >99% radiochemical purity and with no coligands present. This intermediate was then conjugated to adamantane-trimerized GPI (2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)-methyl]pentane-1,5-dioic acid) in 1 step with >95% yield and no need for HPLC purification. The final molecule bound specifically to living human tumor cells expressing PSMA on their surface. Quantitative comparison was made among GPI monomer, GPI trimer, and their 99mTc-derivatives. Conclusion: Our study describes a simple cartridge-based conversion of 99mTc-pertechnetate to a useful, preloaded NHS ester intermediate that takes only 25 min to prepare and results in >99% radiochemical purity. Using this chemistry, we produced a high-specific-activity, 99mTc-labeled, PSMA-targeted small molecule and demonstrate γ-ray radioscintigraphic imaging of living human prostate cancer cells.

Pd-catalyzed assembly of spirooxindole natural products: a short synthesis of horsfiline.

The Pd-catalyzed intramolecular alpha-arylation of amides is applied to the synthesis of functionalized spirooxindoles. The substrate scope is evaluated, and the reaction is demonstrated to be useful for the assembly of spirooxindole natural products and derivatives thereof. As an application, a new synthesis of horsfiline 1 is presented, giving the natural product in only 4 steps from commercially available amino acid 12.

Multivalent scaffolds for affinity maturation of small molecule cell surface-binders and their application to prostate tumor targeting

Adamantane scaffolds for affinity maturation of prostate cancer specific ligands of low molecular mass are described. These scaffolds are modular and can be used for conjugation of up to three ligands and an additional effector molecule by standard peptide coupling techniques. The potential of the scaffolds is demonstrated with the multimerization of GPI 1, a prostate cancer specific small molecule. A detailed study of multimerized GPI conjugates with near-infrared fluorophores and their binding properties to different prostate cancer cell lines shows the specific binding of these conjugates to cell types positive for prostate specific membrane antigen (PSMA). We demonstrate that these conjugates allow the sensitive imaging of prostate cancer cells with NIR methodology and suggest that our adamantane scaffolds might be generally useful for affinity maturation of small molecules targeting cell surface epitopes.

Rigid Multivalent Scaffolds Based on Adamantane

We present two new synthetic strategies to rigid multivalent scaffolds of the general structure 1 based on adamantane. Both routes start from arylated adamantane derivatives and give the target compounds 12 and 18 in 5 and 7 steps, respectively. These scaffolds have been designed for the assembly of multivalent binders for cell surface epitopes. The adamantane nucleus exposes three carboxylic acid groups in a well-defined tripodal geometry for conjugation of targeting ligands. In addition, an amino group at the fourth bridgehead position provides a flexible linker for attachment of effector molecules such as contrast agents, radiotracers, or cytotoxins without interfering with the cell binding process.

Multicomponent synthesis of novel amino acid-nucleobase chimeras : A versatile approach to PNA-monomers

This paper describes a multicomponent approach to novel totally protected precursors of PNA-monomers via Ugi 4CC. The obtained bisamides are converted into several partially protected PNA-monomers or derivatives thereof using three different procedures. Methods for hydrolysis are shown to be dependent on the nature of the isocyano component required for Ugi 4CC. Several novel monomers suitable for oligomer synthesis are prepared demonstrating the high versatility of the reaction sequence.

Biomimetic PEG-catecholates for stabile antifouling coatings on metal surfaces: Applications on TiO2 and stainless steel

Trimeric catecholates have been designed for the stable immobilization of effector molecules on metal surfaces. The design of these catecholates followed a biomimetic approach and was inspired by natural multivalent metal binders, such as mussel adhesion proteins (MAPs) and siderophores. Three catecholates have been conjugated to central scaffolds based on adamantyl or trisalkylmethyl core structures. The resulting triscatecholates have been immobilized on TiO2 and stainless steel. In a proof of concept study we have demonstrated the high stability of the resulting nanolayers at neutral and slightly acidic pH. Furthermore, polyethylene glycol (PEG) conjugates of our triscatecholates have been synthesized and were immobilized on TiO2 and stainless steel. The PEG coated surfaces showed excellent antifouling properties upon exposure to human blood and bacteria as demonstrated by fluorescence microscopy, ellipsometry and a bacterial assay with Staphylococcus epidermidis. In addition, our PEG-triscatecholates showed no cytotoxicity against bone-marrow stem cells on TiO2.

Modified PNAs: a simple method for the synthesis of monomeric building blocks.

The synthesis of PNA-monomers with variations in the substitution pattern using the Ugi-Reaction is described. The one-pot procedure leads to new totally protected PNA-monomers which can be selectively cleaved to N-protected monomeric building blocks for PNA synthesis.

Synthesis of the first enantiomerically pure 3-thiazolines via Asinger reaction

Abstract The first synthesis of an enantiomerically and diastereomerically pure 3-thiazoline via modified Asinger reaction using a galactose derived chiral auxiliary is described. The absolute configuration of this heterocyclic imine has been elucidated via X-ray analysis. In addition, the 3-thiazoline has been successfully derivatized under Ugi conditions.

A biomimetic principle for the chemical modification of metal surfaces: synthesis of tripodal catecholates as analogues of siderophores and mussel adhesion proteins.

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.