Highly Ordered Surface Self-Assembly of Fe4 Single Molecule Magnets.

Single molecule magnets (SMMs) have attracted considerable attention due to low-temperature magnetic hysteresis and fascinating quantum effects. The investigation of these properties requires the possibility to deposit well-defined monolayers or spatially isolated molecules within a well-controlled adsorption geometry. Here we present a successful fabrication of self-organized arrays of Fe4 SMMs on hexagonal boron nitride (h-BN) on Rh(111) as template. Using a rational design of the ligand shell optimized for surface assembly and electrospray as a gentle deposition method, we demonstrate how to obtain ordered arrays of molecules forming perfect hexagonal superlattices of tunable size, from small islands to an almost perfect monolayer. High-resolution low temperature scanning tunneling microscopy (STM) reveals that the Fe4 molecule adsorbs on the substrate in a flat geometry, meaning that its magnetic easy axis is perpendicular to the surface. By scanning tunneling spectroscopy (STS) and density functional theory (DFT) calculations, we infer that the majority- and minority-spin components of the spin-split lowest unoccupied molecular orbital (LUMO) can be addressed separately on a submolecular level.

Synthesis and biological evaluation of optimized inhibitors of the mitotic kinesin Kif18A.

The mitotic spindle, a highly dynamic structure composed of microtubules, mediates the segregation of the previously duplicated genome into the two nascent daughter cells. Errors in this process contribute to pathology including tumor formation. Key for the shape and function of the mitotic spindle are kinesins, molecular motor proteins that convert chemical energy into mechanical work. Due to their fast mode of action, small molecules are valuable tools to dissect the dynamic functions of kinesins during mitosis. In this study, we report the identification of optimized small molecule inhibitors of the mitotic kinesin Kif18A. Using BTB-1, the first identified Kif18A inhibitor, as a lead compound, we synthesized a collection of derivatives. We demonstrate that some of the synthesized derivatives potently inhibited the ATPase activity of Kif18A with a half maximal inhibitory concentration (IC50) value in the low micromolar range. In vitro analysis of a panel of Kif18A-related kinesins revealed that the two most potent compounds show improved selectivity compared to BTB-1. Structure-activity relationship studies identified substituents mediating undesired inhibitory effects on microtubule polymerization. In summary, our study provides key insights into the mechanism of action of BTB-1 and its analogs, which will have a great impact on the further development of highly selective and bioactive Kif18A inhibitors. Since Kif18A is frequently overexpressed in solid tumors, such compounds are not only of great interest for basic research but also have the potential to open up new strategies for the treatment of human diseases.

Synthesis and photoswitching studies of OPE-embedded difurylperfluorocyclopentenes.

We report the synthesis and photochemical behavior of five photochromic molecular switches 7a-e with attached molecular wires based on differently substituted oligo(phenylene ethynylene) (OPE) building blocks. The switchable molecular wires 7a-e were built in a convergent approach from substituted iodotolans 6a-e and 1,2-bis(2-methyl-5-ethynylfuran-3-yl)perfluorocyclopentene 5 by 2-fold Sonogashira coupling. Compound 5 was prepared from the corresponding bis-aldehyde 2 by Wittig-type olefination with [PPh3CHBr2]Br·CH3CN, followed by elimination to the bromoalkyne under mild phase-transfer conditions at 0 °C. Halogen-metal exchange with i-PrMgCl·LiCl and hydrolysis furnished 5 in good overall yield. Substituents R(1) and R(2) in the OPE portion were either electron-withdrawing or electron-donating, and their influence on the photostability and photoswitching characteristics of 7a-e was studied. All resulting molecules show reversible photochromism between the colorless off and the deeply colored on states when irradiated with light of 313 and 576 nm wavelengths, respectively. The quantum yields of these photoreactions increased when electron-withdrawing groups were used. This was further corroborated by reversible protonation/deprotonation of 7e (R(1) = NMe2, R(2) = H) for which the ring-closing quantum yield increased 10-fold upon switching off the donor by protonation.

Features of the behavior of 4-amino-5-carboxamido-1,2,3-triazole in multicomponent heterocyclizations with carbonyl compounds.

Multicomponent reactions involving polyfunctional 4-amino-5-carboxamido-1,2,3-triazole and cyclic carbonyl-containing CH-acids were studied under conventional thermal heating, microwave and ultrasonic irradiation. The features of the reactions studied were discussed and the optimized procedures for the synthesis of final triazolopyrimidines were elaborated. In contrast to the similar MCRs of numerous other aminoazoles, a change of direction of the heterocyclizations in the case of 4-amino-5-carboxamido-1,2,3-triazole was not observed when microwave or thermal heating was substituted by ultrasonication at ambient temperature.

Pronounced effects on switching efficiency of diarylcycloalkenes upon cycloalkene ring contraction.

Several difurylperfluorocyclobutenes showing reversible photochromism were synthesized. In comparison to their cyclopentene homologues they show enhanced quantum yields for ring opening but reduced quantum yields for ring closure. X-ray structure analysis and quantum chemical calculations provide a conclusive explanation for such a behaviour.

Charge transport characteristics of diarylethene photoswitching single-molecule junctions.

We report on the experimental analysis of the charge transport through single-molecule junctions of the open and closed isomers of photoswitching molecules. Sulfur-free diarylethene molecules are developed and studied via electrical and optical measurements as well as density functional theory calculations. The single-molecule conductance and the current-voltage characteristics are measured in a mechanically controlled break-junction system at low temperatures. Comparing the results with the single-level transport model, we find an unexpected behavior of the current-dominating molecular orbital upon isomerization. We show that both the side chains and end groups of the molecules are crucial to understand the charge transport mechanism of photoswitching molecular junctions.

HiTSEE KNIME: a visualization tool for hit selection and analysis in high-throughput screening experiments for the KNIME platform.

We present HiTSEE (High-Throughput Screening Exploration Environment), a visualization tool for the analysis of large chemical screens used to examine biochemical processes. The tool supports the investigation of structure-activity relationships (SAR analysis) and, through a flexible interaction mechanism, the navigation of large chemical spaces. Our approach is based on the projection of one or a few molecules of interest and the expansion around their neighborhood and allows for the exploration of large chemical libraries without the need to create an all encompassing overview of the whole library. We describe the requirements we collected during our collaboration with biologists and chemists, the design rationale behind the tool, and two case studies on different datasets. The described integration (HiTSEE KNIME) into the KNIME platform allows additional flexibility in adopting our approach to a wide range of different biochemical problems and enables other research groups to use HiTSEE.

Synthesis and X-ray structure analysis of a heptacoordinate titanium(IV)-bis-chelate with enhanced in vivo antitumor efficacy.

Chelate stabilization of a titanium(IV)-salan alkoxide by ligand exchange with 2,6-pyridinedicarboxylic acid (dipic) resulted in heptacoordinate complex 3 which is not redox-active, stable on silica gel and has increased aqueous stability. 3 is highly toxic in HeLa S3 and Hep G2 and has enhanced antitumor efficacy in a mouse cervical-cancer model.

Current-voltage characteristics of single-molecule diarylethene junctions measured with adjustable gold electrodes in solution.

We report on an experimental analysis of the charge transport through sulfur-free photochromic molecular junctions. The conductance of individual molecules contacted with gold electrodes and the current-voltage characteristics of these junctions are measured in a mechanically controlled break-junction system at room temperature and in liquid environment. We compare the transport properties of a series of molecules, labeled TSC, MN, and 4Py, with the same switching core but varying side-arms and end-groups designed for providing the mechanical and electrical contact to the gold electrodes. We perform a detailed analysis of the transport properties of TSC in its open and closed states. We find rather broad distributions of conductance values in both states. The analysis, based on the assumption that the current is carried by a single dominating molecular orbital, reveals distinct differences between both states. We discuss the appearance of diode-like behavior for the particular species 4Py that features end-groups, which preferentially couple to the metal electrode by physisorption. We show that the energetic position of the molecular orbital varies as a function of the transmission. Finally, we show for the species MN that the use of two cyano end-groups on each side considerably enhances the coupling strength compared to the typical behavior of a single cyano group.

Cytotoxic dinuclear titanium-salan complexes: structural and biological characterization.

Controlled hydrolysis of donor-substituted titanium-salan complexes led to the formation of well-defined dinuclear complexes. Structure determination by means of X-ray and NMR-studies revealed the presence of a single µ-oxo bridge and one labile alkoxide ligand per titanium center. Concomitant cytotoxicity assays of the isolated dinuclear complexes showed cytotoxicities in the low micro-molar region, surpassing in this respect even their monomeric ancestors, thus making them possible highly active metabolites of titanium-salan anti-cancer drugs.

Charge transport in azobenzene-based single-molecule junctions.

Azobenzene-derivative molecules change their conformation as a result of a cis-trans transition when exposed to ultraviolet or visible light irradiation and this is expected to induce a significant variation in the conductance of molecular devices. Despite extensive investigations carried out on this type of molecule, a detailed understanding of the charge transport for the two isomers is still lacking. We report a combined experimental and theoretical analysis of electron transport through azobenzene-derivative single-molecule break junctions with Au electrodes. Current-voltage and inelastic electron tunneling spectroscopy (IETS) measurements performed at 4.2 K are interpreted based on first-principles calculations of electron transmission and IETS spectra. This qualitative study unravels the origin of a slightly higher conductance of junctions with the cis isomer and demonstrates that IETS spectra of cis and trans forms show distinct vibrational fingerprints that can be used for identifying the isomer.

Synthesis and photoswitching studies of difurylperfluorocyclopentenes with extended π-systems.

In an attempt to design molecular optoelectronic switches functioning in molecular junctions between two metal tips, we synthesized a set of photochromic compounds by extending the π-system of 1,2-bis-(2-methyl-5-formylfuran-3-yl)perfluorocyclopentene through suitable coupling reactions involving the formyl functions, thereby also introducing terminal groups with a binding capacity to gold. Avoiding the presence of gold-binding sulphur atoms in the photoreactive centre, as they are present in the frequently used analogous thienyl compounds, the newly synthesized compounds should be more suitable for the purpose indicated. The kinetics of reversible photoswitching of the new compounds by UV and visible light was quantitatively investigated in solution. The role of conformational flexibility of the π-system for the width of the UV/Vis spectra was clarified by using quantum chemical calculations with time-dependent (TD)-DFT. As a preliminary test of the potential of the new compounds to serve as optoelectronic molecular switches, monolayer formation and photochemical switching on gold surfaces was observed by using surface plasmon resonance.

Titanium salan complexes displays strong antitumor properties in vitro and in vivo in mice.

The anticancer activity of titanium complexes has been known since the groundbreaking studies of Köpf and Köpf-Maier on titanocen dichloride. Unfortunately, possibly due to their fast hydrolysis, derivatives of titanocen dichloride failed in clinical studies. Recently, the new family of titanium salan complexes containing tetradentate ONNO ligands with anti-cancer properties has been discovered. These salan complexes are much more stabile in aqueous media. In this study we describe the biological activity of two titanium salan complexes in a mouse model of cervical cancer. High efficiency of this promising complex family was demonstrated for the first time in vivo. From these data we conclude that titanium salan complexes display very strong antitumor properties exhibiting only minor side effects. Our results may influence the chemotherapy with metallo therapeutics in the future.

The cobalt way to angucyclinones: asymmetric total synthesis of the antibiotics (+)-rubiginone B2, (-)-tetrangomycin, and (-)-8-O-methyltetrangomycin.

A cobalt(I)-mediated convergent and asymmetric total synthesis of angucyclinones with an aromatic B ring has been developed. In the course of our research, we synthesized three naturally occurring anguclinone derivatives, namely, (+)-rubiginone B(2) (1), (-)-8-O-methyltetrangomycin (2), and (-)-tetrangomycin (3). By combining 3-hydroxybenzoic acid, 3-methoxybenzoic acid, citronellal, and geraniol as starting materials in a convergent way, we were able to synthesize chiral triyne chains, which were cyclized with [CpCo(C(2)H(4))(2)] (Cp=cyclopentadienyl) by means of an intramolecular [2+2+2] cycloaddition to their corresponding tetrahydrobenzo[a]anthracenes. Successive oxidation and deprotection steps led to the above-mentioned natural products 1-3.

Dimethyl titanocene Y: a valuable precursor for libraries of cytotoxic titanocene derivatives.

Reaction of the known titanocene Y 2 with methyl lithium at -15 degrees C yields bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dimethyl (dimethyl titanocene Y, 3), a hitherto unknown, surprisingly robust titanium (IV) dimethyl species. Dimethyl titanocene Y was utilized in the preparation of several bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dicarboxylates by the reaction with the free carboxylic acids in fair to good yields. Cytotoxicity of all new compounds has been estimated in Hela S3 cells.

Combined directed ortho metalation-halogen dance (HD) synthetic strategies. HD-anionic ortho fries rearrangement and double HD sequences.

A general and efficient directed ortho metalation (DoM)-halogen dance (HD)-electrophile quench sequence for the synthesis of trisubstituted pyridyl O-carbamates is described. A second HD sequence furnishes highly functionalized tetrasubstituted pyridines. Furthermore, a hitherto unobserved double HD rearrangement is reported. Under similar LDA conditions, aromatic O-carbamates with OMe, Cl, and F substituents (4a-c) undergo either a HD-electrophile quench sequence, 4a-c --> 18-20, or a HD-anionic ortho Fries rearrangement, 4a-c --> 6a-c, respectively.

Cytotoxic titanium salan complexes: surprising interaction of salan and alkoxy ligands.

The synthesis, biochemical evaluation, and hydrolysis studies of a wide selection of alkyl- and halogen-substituted titanium salan alkoxides are presented herein. A systematic change in the employed alkoxides revealed that both the bulk of the salan ligands and the steric demand of the labile ligands are of great importance for the obtained biological activity. Surprisingly, these two factors are not independent from each other; lowering the steric demand of the alkoxide of a hitherto nontoxic complex renders it cytotoxic. Therefore, our data suggest that the overall size of the complex exerts a strong influence on its biological activity. To decide whether the correlation between the cytotoxicity and the steric demand of the whole complex is merely based on an altered hydrolysis or on the interaction with biomolecules, the behavior of selected complexes under hydrolytic conditions and the influence of transferrin were investigated. Complexes differing only in their labile alkoxy ligands gave the same hydrolysis products with similar hydrolysis rates but displayed cytotoxicities that differed in the range of one order of magnitude. Thus, it seems that the hydrolysis product is not the active species but rather that the unhydrolysed complex is important for the first interaction with a biomolecule. This promoted the idea of hydrolysis being a detoxification pathway. In accordance with the above conclusion, chloro-substituted complex [Ti(Ph(Cl)N(Me))(2)(O(iPr))(2)] displayed a high cytotoxicity (IC(50) approximately 5 microM) and surprisingly high hydrolytic stability (t(1/2)=108 h). These findings, together with the observed cytotoxicity in a cisplatin-resistant cell line, make halo-substituted salan complexes an interesting target for further studies.

Titanocene difluorides with improved cytotoxic activity.

Titanocene difluorides can be obtained by halide metathesis of the respective titanocene dichlorides with trimethyltin fluoride (Me(3)SnF), giving access to a new class of cytotoxic active substances. Furthermore, an improved method for the synthesis of diaryl-substituted titanocene dichlorides is presented.

Diversification of a thieno[2,3-d]pyrimidin-4-one scaffold via regioselective alkylation reactions.

The 2-aryl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-ones and 2-aryl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones have been diversified by alkylation reactions, applying benzylchlorides and N-substituted 2-chloroacetamides as alkylating agents. Under the found uniform conditions the substitution direction does not depend on the structure of the alkylating agent and gives monoalkylated products in high yields with simple workup. The alkylation of the 2,3-dihydropyrimidin-4(1H)-one derivatives proceeds onto the N1-position; however, in the case of pyrimidin-4(3H)-ones the O-alkylated products are formed selectively. An alternative strategy for the synthesis of the N1-benzyl-2,3-dihydropyrimidin-4(1H)-one derivatives is also developed. It applies the redaction of N2-substituted Gewald's amides with aromatic aldehydes and allows simple introduction of various substituents in the final molecule.