Synthesis and functional studies of THF-gramicidin hybrid ion channels

THF-gramicidin hybrids 2-4 with the L-THF amino acid 1 in positions 11 and 12 and compounds 5-8 with the D-THF amino acid ent-1 in positions 10 and 11 were synthesized and their ion channel properties were studied by single-channel-current analysis. The replacement of positions 11 and 12 by the L-THF amino acid 1 gave a strongly reduced channel performance. In contrast, replacement of positions 10 and 11 by the D-THF amino acid ent-1 gave rise to new and interesting channel properties. For the permeability ratios, the ion selectivity shifts from Eisenman I towards Eisenman III selectivity and the channels display ms-dynamics. Most remarkable is the asymmetric compound 8, which inserts selectively into a DPhPC membrane and displays voltage-directed gating dynamics.     

Synthesis of Unsubstituted and 4,4′-Substituted Oligobipyridines as Ligand Strands for Helicate Self-Assembly

A general strategy for the synthesis of oligobipyridine ligands 2 – 5 containing from two to five 2,2′-bipyridine subunits, for helical metal complexes is described (sec Scheme). Both the unsubstituted parent strands ( a series) as well as their derivatives bearing fester or amide functions in the 4,4′-positions of the bipyridine moieties ( b – d series) have been obtained.     

Time-resolved fluorescence analysis of the mobile flavin cofactor in p -hydroxybenzoate hydroxylase

Conformational heterogeneity of the FAD cofactor in p-hydroxybenzoate hydroxylase (PHBH) was investigated with time-resolved polarized flavin fluorescence. For binary enzyme/substrate (analogue) complexes of wild-type PHBH and Tyr222 mutants, crystallographic studies have revealed two distinct flavin conformations; the ‘in’ conformation with the isoalloxazine ring located in the active site, and the ‘out’ conformation with the isoalloxazine ring disposed towards the protein surface. Fluorescence-lifetime analysis of these complexes revealed similar lifetime distributions for the ‘in’ and ‘out’ conformations. The reason for this is twofold. First, the active site of PHBH contains various potential fluorescence-quenching sites close to the flavin. Fluorescence analysis of uncomplexed PHBH Y222V and Y222A showed that Tyr222 is responsible for picosecond fluorescence quenching free enzyme. In addition, other potential quenching sites, including a tryptophan and two tyrosines involved in substrate binding, are located nearby. Since the shortest distance between these quenching sites and the isoalloxazine ring differs only little on average, these aromatic residues are likely to contribute to fluorescence quenching. Second, the effect of flavin conformation on the fluorescence lifetime distribution is blurred by binding of the aromatic substrates: saturation with aromatic substrates induces highly efficient fluorescence quenching. The flavin conformation is therefore only reflected in the small relative contributions of the longer lifetimes.     

Click Chemistry in Ultra-high Vacuum – Tetrazine Coupling with Methyl Enol Ether Covalently Linked to Si(001)

The additive-free tetrazine/enol ether click reaction was performed in ultra-high vacuum (UHV) with an enol ether group covalently linked to a silicon surface: Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate molecules were coupled to the enol ether group of a functionalized cyclooctyne which was adsorbed on the silicon (001) surface via the strained triple bond of cyclooctyne. The reaction was observed at a substrate temperature of 380 K by means of X-ray photoelectron spectroscopy (XPS). A moderate energy barrier was deduced for this click reaction in vacuum by means of density functional theory based calculations, in good agreement with the experimental results. This UHV-compatible click reaction thus opens a new, flexible route for synthesizing covalently bound organic architectures.     

Complex Surface Chemistry of an Otherwise Inert Solvent Molecule: Tetrahydrofuran on Si(001)

The reaction of tetrahydrofuran (THF), an otherwise inert solvent molecule, on Si(001) was experimentally studied in ultra‐high vacuum. Using scanning tunneling microscopy (STM) and photoelectron spectroscopy at variable temperature, we could both isolate a datively bound intermediate state of THF on Si(001), as well as the final configuration that bridges two dimer rows of the Si(001) surface after ether cleavage. The latter configuration implies splitting of the O?C bond, which is typically kinetically suppressed. THF thus exhibits a hitherto unknown reactivity on Si(001).     

Apoptolidin: induction of apoptosis by a natural product

Apoptolidin is a natural product that selectively induces apoptosis in several cancer cell lines. Apoptosis, programmed cell death, is a biological key pathway for regulating homeostasis and morphogenesis. Apoptotic misregulations are connected with several diseases, in particular cancer. The extrinsic way to apoptosis leads through death ligands and death receptors to the activiation of the caspase cascade, which results in proteolytic degradation of the cell architecture. The intrinsic pathway transmits signals of internal cellular damage to the mitochondrion, which loses its structural integrity, and forms an apoptosome that initiates the caspase cascade. Compounds which regulate apoptosis are of high medical significance. Many natural products regulate apoptotic pathways, and apoptolidin is one of them. The known synthetic routes to apoptolidin are described and compared in this Review. Selected further natural products which regulate apoptosis are introduced briefly.