A unified strategy for the synthesis of aldohexoses by boronate assisted assembly of CH2X2 derived C1-building blocks.

A synthetic strategy for all aldohexoses with individually addressable protecting groups from dihalomethane C1-units is reported. The underlying synthesis of C6-sugar alcohols relies on three consecutive Matteson sequences, vinylation and bishydroxylation. Erythro and threo isomers have been realized for every glycol motif by strategic variation of the sequence.

A Fluorophore-Labeled Lysine Dendrimer with an Oxo-Anion-Binding Motif for Tracking Gene Transfection.

A transfection vector based on a peptide dendrimer (1) has been developed and its abilities for DNA binding and transport have been investigated. By attaching a fluorophore to the vector system (1*), several steps in the transfection process could be monitored directly. As DLS and AFM studies showed, the labeled vector 1* condensed DNA into tightly packed aggregates able to enter eukaryotic cells. Co-localization experiments revealed that the ligand/plasmid complex is taken up by the endosomal pathway followed by an endosomal escape or lysosomal degradation. Afterwards, the plasmid DNA seems to enter the nucleus due to a breakdown of the nuclear envelope during mitosis, as only cells that have recently undergone mitosis showed H2B-GFP expression.

Advances towards Cell-Specific Gene Transfection: A Small-Molecule Approach Allows Order-of-Magnitude Selectivity.

Invited for the cover of this issue are Christoph Hirschhäuser and his colleagues from the University of Duisburg-Essen. The image depicts a biotin-labelled transfection vector selectively channelling DNA into a cancer cell. The QR code on the label will lead you to a video abstract (https://youtu.be/OgXfBPZTKGA). Read the full text of the article at 10.1002/chem.202104618.

Total Synthesis of Resveratrone and iso-Resveratrone.

The first total synthesis of resveratrone and iso-resveratrone based on an epoxide olefination approach is described. The pivotal reaction proceeds by insertion of the lithiated epoxide into a boronic ester and subsequent syn-elimination. Resveratrone has been described to have remarkable photophysical properties, including two-photon absorption. Therefore, an azide derivative has been prepared to allow for use as a biological label.

Advances towards Cell-Specific Gene Transfection: A Small-Molecule Approach Allows Order-of-Magnitude Selectivity.

A transfection vector that can home in on tumors is reported. Whereas previous vectors that allow moderately cell selective gene transfection used larger systems, this small-molecule approach paved the way for precise structure-activity relationship optimization. For this, biotin, which mediates cell selectivity, was combined with the potent DNA-binding motif tetralysine-guanidinocarbonypyrrol via a hydrophilic linker, thus enabling SAR-based optimization. The new vector mediated biotin receptor (BR)-selective transfection of cell lines with different BR expression levels. Computer-based analyses of microscopy images revealed a preference of one order of magnitude for the BR-positive cell lines over the BR-negative controls.

Reversible Self-Assembly of Gold Nanoparticles Based on Co-Functionalization with Zwitterionic and Cationic Binding Motifs*.

We report a pH- and temperature-controlled reversible self-assembly of Au-nanoparticles (AuNPs) in water, based on their surface modification with cationic guanidiniocarbonyl pyrrole (GCP) and zwitterionic guanidiniocarbonyl pyrrole carboxylate (GCPZ) binding motifs. When both binding motifs are installed in a carefully balanced ratio, the resulting functionalized AuNPs self-assemble at pH 1, pH 7 and pH 13, whereas they disassemble at pH 3 and pH 11. Further disassembly can be achieved at elevated temperatures at pH 1 and pH 13. Thus, we were able to prepare functionalized nanoparticles that can be assembled/disassembled in seven alternating regimes, simply controlled by pH and temperature.

Supramolecular polymers with reversed viscosity/temperature profile for application in motor oils.

We report novel supramolecular polymers, which possess a reversed viscosity/temperature profile. To this end, we developed a series of ditopic monomers featuring two self-complementary binding sites, either the guanidiniocarbonyl pyrrole carboxylic acid (GCP) or the aminopyridine carbonyl pyrrole carboxylic acid (ACP). At low temperatures, small cyclic structures are formed. However, at elevated temperatures, a ring-chain transformation leads to the formation of a supramolecular polymer. We demonstrate that this effect is dependent on the concentration of the solution and on the polarity of the solvent. This effect can counteract the loss of viscosity of the solvent at elevated temperatures, thus opening an application of our systems as viscosity index improvers (VIIs) in working fluids. This was tested for different motor oils and led to the identification of one compound as a promising VII.

A Metallosupramolecular Coordination Polymer for the 'Turn-on' Fluorescence Detection of Hydrogen Sulfide.

A coumarin based probe for the efficient detection of hydrogen sulfide in aqueous medium is reported. The investigated coumarine-based derivative forms spherical nanoparticles in aqueous media. In presence of Pd2+, a metallosupramolecular coordination polymer is formed, which is accompanied by quenching of the coumarin emission at 390 nm. Its Pd2+ complex could be used as a probe for chemoselective detection of monohydrogensulfide (HS-). Presence of HS- leads to a'turn-on' fluorescence signal, resulting from decomplexation of Pd2+ from the metallosupramolecular probe. The probe was successfully applied for qualitative and quantitative detection of HS- in different sources of water directly collected from sea, river, tap and laboratory drain water, as well as in growth media for aquatic species.

Dual pH-Induced Reversible Self-Assembly of Gold Nanoparticles by Surface Functionalization with Zwitterionic Ligands.

The dual pH-induced reversible self-assembly (PIRSA) of Au-nanoparticles (Au NPs) is reported, based on their decoration with the self-complementary guanidiniocarbonyl pyrrole carboxylate zwitterion (GCPZ). The assembly of such functionalized Au NPs is found at neutral pH, based on supramolecular pairing of the GCPZ groups. The resulting self-assembled system can be switched back to the disassembled state by addition of base or acid. Two predominant effects that contribute to the dual-PIRSA of Au NPs are identified, namely the ionic hydrogen bonding between the GCPZ groups, but also a strong hydrophobic effect. The contribution of each interaction is depending on the concentration of GCPZ on NPs, which allows to control the self-assembly state over a wide range of different water/solvent ratios.

Cancer-Cell-Specific Drug Delivery by a Tumor-Homing CPP-Gossypol Conjugate Employing a Tracelessly Cleavable Linker.

Tumor-targeted drug delivery is highly important for improving chemotherapy, as it reduces the dose of cytotoxic agents and minimizes the death of healthy tissues. Towards this goal, a conjugate was synthesized of gossypol and a MCF-7 cancer cell specific CPP (cell penetrating peptide), thus providing a selective drug delivery system. Utilizing the aldehyde moiety of gossypol, the tumor homing CPP RLYMRYYSPTTRRYG was attached through a semi-labile imine linker, which was cleaved in a traceless fashion under aqueous conditions and had a half-life of approximately 10 hours. The conjugate killed MCF-7 cells to a significantly greater extent than HeLa cells or healthy fibroblasts.

Multi-Stimuli-Responsive Supramolecular Polymers Based on Noncovalent and Dynamic Covalent Bonds.

Several modes of supramolecular assembly relying on noncovalent as well as dynamic covalent interactions were combined in a single molecule. The supramolecular self-assembly of 1 can be controlled by three stimuli, namely light, pH, and addition of metal ions, in both organic and aqueous media. The multi-stimuli-responsive nature of 1 was used successfully for the controlled encapsulation and on-demand release of hydrophobic molecules, such as dyes and drugs.

A Selective Cucurbit[8]uril-Peptide Beacon Ensemble for the Ratiometric Fluorescence Detection of Peptides.

A convenient supramolecular strategy for constructing a ratiometric fluorescent chemosensing ensemble, consisting of a macrocyclic host (cucurbit[8]uril CB[8]), and a pyrene-tagged amphiphilic peptide beacon (AP 1), is reported. AP 1 unfolds upon encapsulation of the pyrene termini into the hydrophobic CB[8] cavity. This changes pyrene excimer to monomer emission. Substrates with higher affinity for the CB[8] cavity can displace AP 1 from the ensemble. The released AP 1 folds again to form a pyrene excimer, which allows for the ratiometric fluorescence monitoring of the substrate. In this report, the ensemble capacity for ratiometric fluorescence monitoring of biological substrates, such as amino acid derivatives, specific peptides, and proteins, in aqueous media is demonstrated.

Iterative Synthesis of Alkenes by Insertion of Lithiated Epoxides into Boronic Esters.

The insertion of lithiated epoxides into boronic esters followed by thermal syn-elimination provides a stereospecific entry to alkenes. This process avoids transition metals and is amenable to iteration to provide higher substitution patterns.

A Branched Tripeptide with an Anion-Binding Motif as a New Delivery Carrier for Efficient Gene Transfection.

Branched and dendrimeric cationic peptides have shown better transfection efficiency than linear peptides, owing to their superior capacity for inducing DNA condensation. We have designed and synthesized two analogously guanidinocarbonylpyrrole-substituted (GCP-substituted) branched cationic tripeptides that provide extremely strong electrostatic attraction towards DNA. Both ligands 1 and 2 can bind to DNA and form condensed complexes, owing to the branched structure and high positive charges, as demonstrated by isothermal titration calorimetry (ITC), ζ potential and atomic force microscopy (AFM). After the replacement of the carboxylate group by an amide group, binding of ligand 2 to DNA shows exothermic enthalpy and positive entropy changes relative to ligand 1. Rational interpretation would suggest that ligand 2 might aid the translocation of plasmid pF143 to HEK 293T cells, showing high gene transfection efficiency. This work therefore provides a facile way, by modifying a branched cationic tripeptide with GCP, to turn a peptide even a tripeptide into an efficient gene transfection vector.

Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden.

BACKGROUND: Redox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable. METHODS: Bio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5'-CH2O-TDS substituent. Four of these metal-containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1-transgenic splenocytes. RESULTS: The MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA-evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA-triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (∆ΨM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis. CONCLUSIONS: Redox-active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis.

Nucleoside analogues with a 1,3-diene-Fe(CO)3 substructure: stereoselective synthesis, configurational assignment, and apoptosis-inducing activity.

The synthesis and stereochemical assignment of two classes of iron-containing nucleoside analogues, both of which contain a butadiene-Fe(CO)3 substructure, is described. The first type of compounds are Fe(CO)3-complexed 3'-alkenyl-2',3'-dideoxy-2',3'-dehydro nucleosides (2,5-dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal-assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl-glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson-Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X-ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis-inducing properties (through an unusual caspase 3-independent but ROS-dependent pathway). Furthermore, some structure-activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin-labeled conjugates.

Spiro-fused pyrrolidine, piperidine, and oxindole scaffolds from lactams.

Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described. These three-dimensional frameworks, which conform to the "rule of three", are suitably protected to allow for site-selective manipulation and functionalization. Different modes of substrate control were explored, which allow for good to excellent levels of diastereoselectivity and dispense with the need for additional chiral reagents or catalysts. The concepts developed were applied in short, formal syntheses of (±)-coerulescine and (±)-horsfiline.

Paraoxonase-1 is a major determinant of clopidogrel efficacy.

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

Intramolecular 1,6-addition to 2-pyridones. Mechanism and synthetic scope.

The scope and limitations of the intramolecular 1,6-addition of an enolate to a 2-pyridone moiety, a reaction that has found application in the synthesis of the lupin alkaloids, have been probed. This nucleophilic addition process has been shown to be reversible and favored in the case of (less stabilized) amide and lactam enolates, which readily form five- and six-membered bi-/tricyclic products. Alternative enolates (ketone, ester, thiolactam) and a variety of different acceptors (isoquinolinone, pyrimidinone, pyrazinone, pyridopyrazinone) have been evaluated, and a range of competing side reactions have been identified and characterized using various techniques, including in situ IR.