Towards π-wires on a semiconductor surface: Benzyne on Si(001).

Towards the goal of covalently bound molecular wires on silicon, the adsorption of benzyne on Si(001) was studied by means of scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), and density functional calculations (DFT). The benzyne molecule is found to adsorb preferentially via the strained triple bond on one dimer of the Si(001) surface which results in an intact π system covalently bound to the surface. With increasing coverage, the molecules primarily adsorb along the dimer rows; on stepped surfaces, these molecular wires are all oriented in the same direction.

Formation of Si/organic interfaces using alkyne-functionalized cyclooctynes-precursor-mediated adsorption of linear alkynes versus direct adsorption of cyclooctyne on Si(0 0 1).

Adsorption of ethynyl-cyclopropyl-cyclooctyne (ECCO), an alkyne-functionalized cyclooctyne, on Si(0 0 1) was studied by means of x-ray photoelectron spectroscopy (XPS) and scanning tunneling microscopy (STM). Together, XPS and STM results clearly indicate chemoselective adsorption of ECCO on Si(0 0 1) via a [2+2] cycloaddition of the strained triple bond of cyclooctyne without reaction of the ethynyl group. The results are compared to the adsorption of acetylene on Si(0 0 1): C2H2 adsorbs on Si(0 0 1) via a precursor-mediated reaction channel as it was shown by means of temperature dependent measurements of the sticking probability as well as by means of STM experiments at variable temperature. On the other hand, cyclooctyne adsorbs on Si(0 0 1) via a direct reaction channel. This qualitative difference in the reaction pathways of the two functionalities leads to the observed chemoselective adsorption of ECCO via the strained triple bond of cyclooctyne. As the ethynyl group stays intact, monolayers of ECCO on Si(0 0 1) form a well defined interface between the silicon substrate and further organic molecular layers which can be attached to the ethynyl functionality.

A light-triggered transmembrane porin.

Porins are ideal model systems for channel engineering. OmpG is a robust, monomeric, transmembrane ß-barrel without ion selectivity. Here, we present a photocaged diethylaminocoumarin (DEACM) hybrid of OmpG. Blockage of the pore by DEACM is confirmed by reduced conductivity. An optimal effect was obtained when two bulky butyl-substituted coumarin cages were attached on the inside of the pore. Irradiation at 385 nm removed the photocages, leading to a restoration of channel conductivity.

Probing membrane protein orientation and structure using fast magic-angle-spinning solid-state NMR.

One and two-dimensional solid-state NMR experiments are discussed that permit probing local structure and overall molecular conformation of membrane-embedded polypeptides under Magic Angle Spinning. The functional dependence of a series of anisotropic recoupling schemes is analyzed using theoretical and numerical methods. These studies lead to the construction of a set of polarization dephasing or transfer units that probe local backbone conformation and overall molecular orientation within the same NMR experiment. Experimental results are shown for a randomly oriented peptide and for two model membrane-peptides reconstituted into lipid bilayers and oriented on polymer films according to a method proposed by Bechinger et al.

Molecular signal transduction by conformational transmission: use of tetrasubstituted perhydroanthracenes as transducers.

2,3,6,7-Tetrasubstituted cis-anti-cis perhydroanthracenes have been studied as conformational transducers for molecular signal transduction. 2,2'-Bipyridine groups attached to the perhydroanthracene through ether linkages were chosen as receptor substituents, while pyrene groups were selected as effectors. A chelation-induced triple ring flip of the perhydroanthracene could be achieved by the complexation of zinc(II) ions at the bipyridine sites of ligands 13 and 15. It was found that two pyrene substituents attached to the perhydroanthracene via a linker with an E double bond and an ester group could be used to monitor the triple ring flip. In the equatorial positions, the pyrenes are sufficiently close to form an excimer in the excited state, giving a fluorescence signal at 480 nm. In the axial positions, they are far away from each other and give mainly a monomer fluorescence signal at 380 nm. Both the bipyridine receptor and the pyrene effector are present in compound 33. The conformational switching 34-->35 (the two conformers of 33) has successfully been used for a signal transduction over a signal distance of 2 nm.

Quinone-annonaceous acetogenins: synthesis and complex I inhibition studies of a new class of natural product hybrids.

The natural product hybrids quinone-mucocin and quinone- squamocin D were synthesized. In these hybrids, the butenolide unit of the annonaceous acetogenins mucocin and squamocin D is exchanged for the quinone moiety of the natural complex I substrate ubiquinone. For both syntheses, a modular, highly convergent approach was applied. Quinone-mucocin was constructed out of a tetrahydropyran (THP) component 1, a tetrahydrofuran (THF) unit 2, and a quinone precursor 3. A stereoselective, organometallic coupling reaction was chosen for the addition of the THP unit to the rest of the molecule. In the final step, the oxidation to the free quinone was achieved by using cerium(IV) ammonium nitrate (CAN) as the oxidizing agent. Quinone-squamocin D was assembled in a similar manner, from the chiral side chain bromide 16, the central bis-THF core 17, and the quinone precursor 18. Inhibition of complex I (isolated from bovine heart mitochondria) by the quinone acetogenins and several smaller building blocks was examined; quinone mucocin and quinone-squamocin D act as strong inhibitors of complex I. These results and the data from the smaller substructures indicate that other substructures of the acetogenins besides the butenolide group, such as the polyether component and the lipophilic left-hand side chain, are necessary for the strong binding of the acetogenins to complex I.

Matching organic libraries with protein-substructures.

We present a general approach which allows automatic identification of sub-structures in proteins that resemble given three-dimensional templates. This paper documents its success with non-peptide templates such as beta-turn mimetics. We considered well-tested turn-mimetics such as the bicyclic turned dipeptide (BTD), spiro lactam (Spiro) and the 2,5-disubstituded tetrahydrofuran (THF), a new furan-derivative which was recently developed and characterized. The detected geometric similarity between the templates and the protein patches corresponds to r.m.s.-values of 0.3 A for more than 80% of the constituting atoms, which is typical for active site comparisons of homologous proteins. This fast automatic procedure might be of biomedical value for finding special mimicking leads for particular protein sub-structures as well as for template-assembled synthetic protein (TASP) design.

A convergent total synthesis of (-)-mucocin: an acetogenin from Annonaceae.

A total synthesis of the Annonaceous acetogenin mucocin has been accomplished. The synthesis follows a convergent strategy, wherein at a very late stage the left part of the molecule is connected with the right part. The key reaction is the stereocontrolled addition of an organomagnesium compound 2 to the aldehyde 3. The THP ring of mucocin is build by a 6-endo epoxide cyclization of an epoxyacetonide precursor (16 --> 17). The new modular synthetic approach developed herein should be useful for the synthesis of other related natural products as well as pharmacologically interesting analogues.

Synthesis and biological evaluation of integrin antagonists containing trans- and cis-2,5-disubstituted THF rings.

The synthesis of a series of RGD mimetics is described. All compounds consist of a central 2,5-disubstituted tetrahydrofuran core, a variable linker to a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylene chain (type A, compounds 14, 15, 16, and 17), a four-atom methylene chain with an additional chiral center, and a nitrogen substituent (type B, compounds 38, 39, and 40), and an amide linker of different length with an additional chiral center (type C, compounds 59, 60, 61, and 62). A variety of compounds were tested as potential integrin antagonists in a receptor binding assay (alphaIIbbeta3, alphavbeta3, and alphavbeta5). The relative and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity. Compound 14 proved to be a selective inhibitor of alphaIIbbeta3 (IC50=20nM), whereas compound 40 exhibited high activity for binding of alphaIIbbeta3 (IC50=67nM) and alphavbeta3 (IC50=52nM).

(1R*,2R*)-1,2-(2,3-Dimethoxybutane-2,3-dioxy)cyclohexane.

The title compound, 2,3-dimethoxy-2,3-dimethyl-5,6,7,8-tetrahydro-4-oxachroman, C(12)H(22)O(4), was synthesized as a model compound for substituted diequatorial fixed vicinal trans-cyclohexanediols.

DNH deoxyribonucleohelicates: self assembly of oligonucleosidic double-helical metal complexes.

Nucleic acids, because of their key biological role, are prime targets for the design of either analogues that may mimic some of their features or of complementary ligands that may selectively bind to and react with them for regulation or reaction. Whereas there has been much work on the latter topic since the elucidation of the double-helical structure of DNA, comparatively little has been done on structural and/or functional models, probably owing to the lack of self-organizing molecular systems. Here we present a class of artificial systems, the nucleohelicates, which are of interest from both points of view because they combine the double-helical structure of the double-stranded metal complexes, the helicates, with the selective interaction features of nucleic-acid bases. These functionalized species allow the study of structural effects on the formation of the double helix and on the binding to other entities, in particular to nucleic acids.