Binding Cofactors with Triplex‐Based DNA Motifs

Cofactors are pivotal compounds for the cell and many biotechnological processes. It is therefore interesting to ask how well cofactors can be bound by oligonucleotides designed not to convert but to store and release these biomolecules. Here we show that triplex‐based DNA binding motifs can be used to bind nucleotides and cofactors, including NADH, FAD, SAM, acetyl CoA, and tetrahydrofolate (THF). Dissociation constants between 0.1 μM for SAM and 35 μM for THF were measured. A two‐nucleotide gap still binds NADH. The selectivity for one ligand over the others can be changed by changing the sequence of the binding pocket. For example, a mismatch placed in one of the two triplets adjacent to the base‐pairing site changes the selectivity, favoring the binding of FAD over that of ATP. Further, changing one of the two thymines of an A‐binding motif to cytosine gives significant affinity for G, whereas changing the other does not. Immobilization of DNA motifs gives beads that store NADH. Exploratory experiments show that the beads release the cofactor upon warming to body temperature.     

Structural Aspects of Copper‐Mediated Atom Transfer Radical Polymerization with a Novel Tetradentate Bisguanidine Ligand

This contribution reports the synthesis of the novel tetradentate bisguanidine ligand 2′,2′‐[ethane‐1, 2‐diylbis(methylazanediyl)]bis(ethane‐2, 1‐diyl)bis(1, 1, 3, 3‐tetramethylguanidine) ( L1 , TMG₂dmtrien), which combines two weak amine and two strong guanidine donor functions. Two new copper(II) complexes were isolated and structurally characterized as complexes [Cu(TMG₂dmtrien)][Br]₂ · 3MeCN ( C1 [Br]₂ · 3MeCN) and [Cu(TMG₂dmtrien)][Cl]₂ · 3MeCN ( C2 [Cl]₂ · 3MeCN). The cations C1 and C2 [Cu(TMG₂dmtrien)]²⁺ show a square‐planar coordination environment and are chiral with both enantiomers being observed in the unit cell. We investigated the application of L1 in copper‐mediated styrene ATRP. L1 shows with CuBr and PEBr as initiator a high polymerization activity according to the polymerization rate. First order kinetics confirm the living character of the polymerization. However, the deviation of molecular weights from theoretical molecular weights and the broad molecular weight distributions hint for a low controlled ATRP. The ATRP with further copper(I) salts {CuCl, [Cu(MeCN)₄]BF₄ and [Cu(MeCN)₄]PF₆} and PECl and PEBr as initiators were investigated as well. Herein the use of [Cu(MeCN)₄]PF₆ with PECl led to promising results.     

Exploratory Study on the RNA‐Binding Structural Motifs by Library Screening Targeting pre‐miRNA‐29 a

The metabolic stream of microRNA (miRNA) production, the so‐called maturation process of miRNAs, became one of important metabolic paths for drug‐targeting to modulate the expression of genes related to a number of diseases. We carried out discovery studies on small molecules binding to the precursor of miR‐29a (pre‐miR‐29a) from a chemical library containing 41 119 compounds (AQ library) by the fluorescent indicator displacement (FID) assay using the xanthone derivative X2SdiMe as a fluorescent indicator. The FID assay provided 1075 compounds, which showed an increase of fluorescence. These compounds were subsequently submitted to a binding analysis in a surface plasmon resonance (SPR) assay on a pre‐miR‐29a immobilized surface. 21 hit compounds were identified with a good reproducibility in the binding. These compounds have not been reported to bind to RNA until now and can be classified into two groups on the basis of the kinetics in the binding. To gain more information on the motif structures that could be necessary for the binding to pre‐miR‐29a, 19 substructures were selected from the hit compounds. The substructure library (SS library) which consisted of 362 compounds was prepared from the AQ library. An SPR assay of the SS library on pre‐miR‐29a‐immobilized surface suggested that five substructures could potentially be important structural motifs to bind to pre‐miR‐29a. These studies demonstrate that the combination of FID‐based screening of chemical library and subsequent SPR assay would be one way for obtaining practical solutions for the discovery of molecules which bind to the target pre‐miRNAs.     

Cyclodextrins 3‐Functionalized with 8‐Hydroxyquinolines: Copper‐Binding Ability and Inhibition of Synuclein Aggregation

Neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are multifactorial disorders related to protein aggregation, metal dyshomeostasis, and oxidative stress. To advance understanding in this area and to contribute to therapeutic development, many efforts have been directed at devising suitable agents that can target metal ions associated with relevant biomolecules such as α‐synuclein. This paper presents a new cyclodextrin–8‐hydroxyquinoline conjugate and discusses the properties of four cyclodextrins 3‐functionalized with 8‐hydroxyquinoline as copper(II) chelators and inhibitors of copper‐induced synuclein aggregation. The encouraging results establish the potential of cyclodextrin–8‐hydroxyquinoline conjugates as chelators for the control of copper toxicity.     

Macrocyclic DNA‐Mismatch‐Binding Ligands: Structural Determinants of Selectivity

A collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by one‐ or two‐step condensation of aromatic dialdehydes with aliphatic diamines; notably, the heterodimeric scaffolds were synthesized for the first time. The binding of these macrocycles to DNA duplexes containing a mispaired thymine residue (TX), as well as to the fully paired control (TA), was investigated by thermal denaturation and fluorescent‐intercalator‐displacement experiments. The bisnaphthalene derivatives, in particular, the 2,7‐disubstituted ones, have the highest selectivity for the TX mismatches, as these macrocycles show no apparent binding to the fully paired DNA. By contrast, other macrocyclic ligands, as well as seven conventional DNA binders, show lesser or no selectivity for the mismatch sites. The study demonstrates that the topology of the ligands plays a crucial role in determining the mismatch‐binding affinity and selectivity of the macrocyclic bisintercalators.     

Modification of Supramolecular Binding Motifs Induced By Substrate Registry: Formation of Self‐Assembled Macrocycles and Chain‐Like Patterns

The self‐assembly properties of two Zn^II porphyrin isomers on Cu(111) are studied at different coverage by means of scanning tunneling microscopy (STM). Both isomers are substituted in their meso‐positions by two voluminous 3,5‐di(tert‐butyl)phenyl and two rod‐like 4′‐cyanobiphenyl groups, respectively. In the trans‐isomer, the two 4′‐cyanobiphenyl groups are opposite to each other, whereas they are located at right angle in the cis‐isomer. For coverage up to one monolayer, the cis‐substituted porphyrins self‐assemble to form oligomeric macrocycles held together by antiparallel CN???CN dipolar interactions and CN???H‐C(sp²) hydrogen bonding. Cyclic trimers and tetramers occur most frequently but everything from cyclic dimers to hexamers can be observed. Upon annealing of the samples at temperatures >150 °C, dimeric macrocyclic structures are observed, in which the two porphyrins are bridged by Cu atoms, originating from the surface, under formation of two CN???Cu???NC coordination bonds. The trans‐isomer builds up linear chains on Cu(111) at low coverage, whereas for higher coverage the molecules assemble in a periodic, densely packed structure. Both cis‐ and trans‐bis(4′‐cyanobiphenyl)‐substituted Zn^II porphyrins behave very differently on Cu(111) compared to similar porphyrins in literature on less reactive surfaces such as Au(111) and Ag(111). On the latter surfaces, there is no signal visible between molecular orientation and the crystal directions of the substrate, whereas on Cu(111), very strong adsorbate–substrate interactions have a dominating influence on all observed structures. This strong porphyrin–substrate interaction enables a much broader variety of structures, including also less favorable intermolecular bonding motifs and geometries.     

Sequence‐Defined Introduction of Hydrophobic Motifs and Effects in Lectin Binding of Precision Glycomacromolecules

This study investigates the influence of an increasingly hydrophobic backbone of multivalent glycomimetics based on sequence‐defined oligo(amidoamines) on their resulting affinity toward bacterial lectins. Glycomacromolecules are obtained by stepwise assembly of tailor‐made building blocks on solid support, using both hydrophobic aliphatic and aromatic building blocks to enable a gradual change in hydrophobicity of the backbone. Their binding behavior toward model lectin Concanavalin A (ConA) is evaluated using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) showing higher affinities for glycomacromolecules with higher content of hydrophobic and aromatic moieties in the backbone. Finally, glycomacromolecules are tested in a bacterial adhesion inhibition study against Escherichia coli where more hydrophobic backbones yield higher inhibitory potentials most likely due to additional secondary interactions with hydrophobic regions of the protein receptor as well as a change in conformation exposing carbohydrate ligands for increased binding. Overall, the results highlight the influence and thereby importance of the polymer backbone itself on the resulting properties of polymeric biomimetics.     

Copper‐Catalyzed Deaminative Difluoromethylation

The difluoromethyl group (CF₂H) is considered to be a lipophilic and metabolically stable bioisostere of an amino (NH₂) group. Therefore, methods that can rapidly convert an NH₂ group into a CF₂H group would be of great value to medicinal chemistry. We report herein an efficient Cu‐catalyzed approach for the conversion of alkyl pyridinium salts, which can be readily synthesized from the corresponding alkyl amines, to their alkyl difluoromethane analogues. This method tolerates a broad range of functional groups and can be applied to the late‐stage modification of complex amino‐containing pharmaceuticals.     

Enantioselective Copper‐Catalyzed Quinoline Alkynylation

A highly enantioselective copper‐catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole‐based chiral biaryl P,N ligand, and copper bromide to effect a three‐component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)‐galipinine, (+)‐angustureine, and (?)‐cuspareine are reported.     

Copper‐Catalyzed Borylcupration of Allenylsilanes

A highly regio‐ and stereoselective copper‐catalyzed borylcupration of 1,2‐allenylsilanes affords an unexpected regioreversed allylic boronate bearing an extra C?Si bond at the 3‐position, with a thermodynamically disfavored Z geometry. Such stereodefined allylic boronates containing an extra alkenyl silane moiety are very useful organodimetallic reagents for organic synthesis.