C-Terminal Decarboxylation of Proline-Derived Building Blocks for Protein-Binding Peptides.

Using a set of conformationally restricted Proline-derived Modules (ProMs), our group has recently succeeded in developing inhibitors for the enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain, which is a key mediator of cell migration and plays an important role in tumor metastasis. While these (formally) pentapeptidic compounds show nanomolecular binding affinities towards EVH1, their drug-like properties and cell permeability need to be further optimized before they can be clinically tested as therapeutic agents against metastasis. In this study, we sought to improve these properties by removing the C-terminal carboxylic acid function of our peptoids, either by late-stage decarboxylation or by direct synthesis.

Easy Synthetic Access to High-Melting Sulfurated Copolymers and their Self-Assembling Diblock Copolymers from Phenylisothiocyanate and Oxetane.

Although sulfurated polymers promise unique properties, their controlled synthesis, particularly when it comes to complex and functional architectures, remains challenging. Here, we show that the copolymerization of oxetane and phenyl isothiocyanate selectively yields polythioimidocarbonates as a new class of sulfur containing polymers, with narrow molecular weight distributions (M=5-80 kg/mol with Đ≤1.2; M=124 kg/mol) and high melting points of up to 181 °C.

A pH-Sensitive Double Chromophore Fluorescent Dye for Live-Tracking of Lipophagy.

Lipid droplet (LD) degradation provides metabolic energy and important building blocks for various cellular processes. The two major LD degradation pathways include autophagy (lipophagy), which involves delivery of LDs to autolysosomes, and lipolysis, which is mediated by lipases. While abnormalities in LD degradation are associated with various pathological disorders, our understanding of lipophagy is still rudimentary.

A first-in-class β-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer.

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells.

A Closed-Loop Recyclable Low-Density Polyethylene.

Low-density polyethylene (LDPE) is one of the most important plastics, which is produced unfortunately under extreme conditions. In addition, it consists of robust aliphatic C─C bonds which are challenging to cleave for plastic recycling. A low-pressure and -temperature (p = 2 bara, T = 70 °C) macromonomer-based synthesis of long chain branched polyethylene is reported.

Design of an aryne-platform for the synthesis of non-racemic heterocyclic allocolchicinoids.

A four-step semisynthetic approach towards a highly versatile allocolchicine-related chiral aryne intermediate starting from naturally occurring colchicine was developed, and some of its synthetic transformations were studied. The generated benzyne intermediate afforded a number of non-racemic heterocyclic allocolchicinoids, which were shown to exhibit potent cytotoxicity towards COLO 357, OSA and Raji cells. The proposed methodology is attractive for the synthesis of libraries of new cytotoxic tubulin inhibitors.

Divergent total synthesis of the revised structures of marine anti-cancer meroterpenoids (+)-dysiherbols A-E.

We report here a concise and divergent enantioselective total synthesis of the revised structures of marine anti-cancer sesquiterpene hydroquinone meroterpenoids (+)-dysiherbols A-E (6-10) using dimethyl predysiherbol 14 as a key common intermediate. Two different improved syntheses of dimethyl predysiherbol 14 were elaborated, one starting from Wieland-Miescher ketone derivative 21, which is regio- and diastereoselectively α-benzylated prior to establishing the 6/6/5/6-fused tetracyclic core structure through intramolecular Heck reaction. The second approach exploits an enantioselective 1,4-addition and a Au-catalyzed double cyclization to build-up the core ring system.

Isotope-labeled ergothioneine clarifies the mechanism of reaction with singlet oxygen.

Recently we have uncovered a non-enzymatic multi-step cycle for the regeneration of ergothioneine (ET), after reaction with noxious singlet oxygen (O), by glutathione (GSH). When living cells were loaded with ET labeled with deuterium and N-15 atoms (D5-ET) and exposed to light in the presence of a photosensitizer, no loss of deuterium at position 5 of the imidazole ring was observed, in contradiction to our previous mechanistic proposal. Therefore, it was necessary to reexamine the in vitro products of ET and O by liquid chromatography coupled to high resolution mass spectrometry.

Design and synthesis of a tetracyclic tripeptide mimetic frozen in a polyproline type II (PP2) helix conformation.

A synthesis of the new tetracyclic scaffold ProM-19, which represents a XPP tripeptide unit frozen in a PPII helix conformation, was developed. As a key building block, -Boc-protected ethyl (1,3,4)-2-azabicyclo[2.2.

An organometallic analogue of combretastatin A-4 and its apoptosis-inducing effects on lymphoma, leukemia and other tumor cells .

Hexacarbonyl[1,3-dimethoxy-5-((4'-methoxyphenyl)ethynyl)benzene]dicobalt (NAHO27), an organometallic analogue of combretastatin A-4, has been synthesized and its activity against lymphoma, leukemia, breast cancer and melanoma cells has been investigated. It was shown that NAHO27 specifically induces apoptosis in BJAB lymphoma and Nalm-6 leukemia cells at low micromolar concentration and does not affect normal leukocytes . It also proved to be active against vincristine and daunorubicin resistant leukemia cell lines with p-glycoprotein-caused multidrug resistance and showed a pronounced (550%) synergistic effect when co-applied with vincristine at very low concentrations.

Surface-Compartmentalized Micelles by Stereocomplex-Driven Self-Assembly.

The unique corona structure of surface-compartmentalized micelles (Janus micelles, patchy micelles) opens highly relevant applications, e.g. as efficient particulate surfactants for emulsion stabilization or compatibilization of polymer blends.

Phenanthroindolizidine Alkaloids Isolated from as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant : -methyltylophorinidine () and its five derivatives tylophorinidine (), tylophoridicine E (), 2-demethoxytylophorine (), tylophoridicine D (), and anhydrodehydrotylophorinidine ().

Synthesis and Biological Evaluation of Water-Soluble Esterase-Activated CO-Releasing Molecules Targeting Mitochondria.

Due to the beneficial effects of carbon monoxide as a cell-protective and anti-inflammatory agent, CO-releasing molecules (CORMs) offer some promising potential applications in medicine. In this context, we synthesized a set of acyloxy-cyclohexadiene-Fe(CO) complexes, all displaying a N-methyl-pyridinium triflate moiety in the ester side chain, as mitochondria-targeting esterase-triggered CORM prodrugs. Whereas the compounds in which the acyloxy substituent is attached to the 2-position of the diene-Fe(CO) unit (A series) spontaneously release CO upon dissolution in phosphate buffer, which remarkably is partly suppressed in the presence of porcine liver esterase (PLE), the 1-substituted isomers (B series) show the expected PLE-induced release of CO (up to 3 equiv.

Functional Mesostructured Electrospun Polymer Nonwovens with Supramolecular Nanofibers.

Functional, hierarchically mesostructured nonwovens are of fundamental importance because complex fiber morphologies increase the active surface area and functionality allowing for the effective immobilization of metal nanoparticles. Such complex functional fiber morphologies clearly widen the property profile and enable the preparation of more efficient and selective filter media. Here, the realization of hierarchically mesostructured nonwovens with barbed wire-like morphology is demonstrated by combining electrospun polystyrene fibers, decorated with patchy worm-like micelles, with solution-processed supramolecular short fibers composed of 1,3,5-benzenetricarboxamides with peripheral N,N-diisopropylaminoethyl substituents.

Block Copolymers with Crystallizable Blocks: Synthesis, Self-Assembly and Applications.

Block copolymers with crystallizable blocks are a highly interesting class of materials owing to their unique self-assembly behaviour both in bulk and solution. This Special Issue brings together new developments in the synthesis and self-assembly of semicrystalline block copolymers and also addresses potential applications of these exciting materials.

Realizing shape and size control for the synthesis of coordination polymer nanoparticles templated by diblock copolymer micelles.

The combination of polymers with nanoparticles offers the possibility to obtain customizable composite materials with additional properties such as sensing or bistability provided by a switchable spin crossover (SCO) core. For all applications, a precise control over size and shape of the nanomaterial is highly important as it will significantly influence its final properties. By confined synthesis of iron(II) SCO coordination polymers within the P4VP cores of polystyrene--poly(4-vinylpyridine) (PS--P4VP) micelles in THF we are able to control the size and also the shape of the resulting SCO nanocomposite particles by the composition of the PS--P4VP diblock copolymers (dBCPs) and the amount of complex employed.

Self-Assembled Fluorescent Block Copolymer Micelles with Responsive Emission.

Responsive fluorescent materials offer a high potential for sensing and (bio-)imaging applications. To investigate new concepts for such materials and to broaden their applicability, the previously reported non-fluorescent zinc(II) complex [Zn(L)] that shows coordination-induced turn-on emission was encapsulated into a family of non-fluorescent polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) diblock copolymer micelles leading to brightly emissive materials. Coordination-induced turn-on emission upon incorporation and ligation of the [Zn(L)] in the P4VP core outperform parent [Zn(L)] in pyridine solution with respect to lifetimes, quantum yields, and temperature resistance.

B-nor-methylene Colchicinoid PT-100 Selectively Induces Apoptosis in Multidrug-Resistant Human Cancer Cells via an Intrinsic Pathway in a Caspase-Independent Manner.

Colchicine, the main active alkaloid from L., is a potent tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising biological activities.

: conjugation with a CO-releasing unit greatly enhances the anti-inflammatory activity of itaconates.

Endogenous itaconate as well as the gasotransmitter CO have recently been described as powerful anti-inflammatory and immunomodulating agents. However, each of the two agents comes along with a major drawback: Whereas itaconates only exert beneficial effects at high concentrations above 100 μM, the uncontrolled application of CO has strong toxic effects. To solve these problems, we designed hybrid prodrugs, itaconates that are conjugated with an esterase-triggered CO-releasing acyloxycyclohexadiene-Fe(CO) unit ().

Morphology and Degradation of Multicompartment Microparticles Based on Semi-Crystalline Polystyrene--Polybutadiene--Poly(-lactide) Triblock Terpolymers.

The confinement assembly of block copolymers shows great potential regarding the formation of functional microparticles with compartmentalized structure. Although a large variety of block chemistries have already been used, less is known about microdomain degradation, which could lead to mesoporous microparticles with particularly complex morphologies for ABC triblock terpolymers. Here, we report on the formation of triblock terpolymer-based, multicompartment microparticles (MMs) and the selective degradation of domains into mesoporous microparticles.

Head-to-Head Comparison of Selected Extra- and Intracellular CO-Releasing Molecules on Their CO-Releasing and Anti-Inflammatory Properties.

Over the past decade, a variety of carbon monoxide releasing molecules (CORMs) have been developed and tested. Some CORMs spontaneously release CO once in solution, while others require a trigger mechanism to release the bound CO from its molecular complex. The modulation of biological systems by CORMs depends largely on the spatiotemporal release of CO, which likely differs among the different types of CORMs.

ET-CORM Mediated Vasorelaxation of Small Mesenteric Arteries: Involvement of Kv7 Potassium Channels.

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein.

Janus Micelles by Crystallization-Driven Self-Assembly of an Amphiphilic, Double-Crystalline Triblock Terpolymer.

Surface-compartmentalized micellar nanostructures (Janus and patchy micelles) have gained increasing interest due to their unique properties opening highly relevant applications, e.g., as efficient particulate surfactants, compatibilizers in polymer blends, or templates for catalytically active nanoparticles.

Total Synthesis of (+)-Erogorgiaene and the Pseudopterosin A-F Aglycone via Enantioselective Cobalt-Catalyzed Hydrovinylation.

Due to their pronounced bioactivity and limited availability from natural resources, metabolites of the soft coral Pseudopterogorgia elisabethae, such as erogorgiaene and the pseudopterosines, represent important target molecules for chemical synthesis. We have now developed a particularly short and efficient route towards these marine diterpenes exploiting an operationally convenient enantioselective cobalt-catalyzed hydrovinylation as the chirogenic step. Other noteworthy C-C bond forming transformations include diastereoselective Lewis acid-mediated cyclizations, a Suzuki coupling and a carbonyl ene reaction.