The unsubstituted ortho-amidino benzoic acid : crystal structure, characterization and pKa determination
2017, Hordiyenko, Olga V., Biitseva, Angelina V., Kostina, Yuliya Yu., Zubatyuk, Roman I., Shishkin, Oleg V., Groth, Ulrich, Kornilov, Mikhail Yu.
The simplest o-amidino benzoic acid—2-(amino(imino)methyl)benzoic acid—has been isolated in 23 % yield as a side product of the reaction of phthalonitrile and ammonia along with desired 1-imino-1H-isoindol-3-amine. This amidino acid was fully characterized by nuclear magnetic resonance, IR spectroscopy, mass spectrometry; pKa values were also determined. X-ray diffraction study and quantum chemical calculations revealed that in the solid state it exists as a zwitterion that is stabilized by intermolecular hydrogen bonds.
Synthesis and Biological Evaluation of Optimized Inhibitors of the Mitotic Kinesin Kif18A
2015, Braun, Joachim, Möckel, Martin M., Strittmatter, Tobias, Marx, Andreas, Groth, Ulrich, Mayer, Thomas U.
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
2013-09-06, Wolf, Jannic, Eberspächer, Iris, Groth, Ulrich, Huhn, Thomas
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 R1 and R2 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 (R1 = NMe2, R2 = H) for which the ring-closing quantum yield increased 10-fold upon switching off the donor by protonation.
Pronounced effects on switching efficiency of diarylcycloalkenes upon cycloalkene ring contraction
2012-11-28, Sysoiev, Dmytro, Yushchenko, Tetyana, Scheer, Elke, Groth, Ulrich, Steiner, Ulrich, Exner, Thomas E., Huhn, Thomas
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.
Highly Ordered Surface Self-Assembly of Fe4 Single Molecule Magnets
2015-06-18, Erler, Philipp, Schmitt, Peter, Barth, Nicole, Irmler, Andreas, Bouvron, Samuel, Huhn, Thomas, Groth, Ulrich, Pauly, Fabian, Gragnaniello, Luca, Fonin, Mikhail
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.
α-Thioalkylation of Zinc Dienolates as an Entry to 4-Substituted 1-tert-Butoxy-7a-methylhexahydroindenes
2015, Köhler, Thomas, Huhn, Thomas, Groth, Ulrich
Hexahydroindenes 10 are readily available in 3 steps with an overall yield of 41 – 45 % starting from the Hajos Wiechert ketone 1. Alkylation of the α,β-unsaturated ketone 1 at C-4 has been achieved by thioalkylation of the corresponding zinc dienolate 2 with α-chlorosulfides of type 3. Subsequent in situ reduction and desulfurization of the β-(phenylthio) ketones 4 leads directly to the 4-substituted hexahydroindene-5-ols 6 which can be deoxygenated via their mesylates to the hexahydroindenes 10.
A One‐Pot Synthesis of 3‐Amino‐1H‐isoindol‐1‐one thiazol‐2‐ylhydrazones
2013-08-27, Biitseva, Angelina, Groth, Ulrich, Hordiyenko, Olga
A reaction of phthalonitrile with thiosemicarbazide and α‐haloketones proceeded in one‐pot, giving rise to 3‐amino‐1H‐isoindol‐1‐one thiazol‐2‐ylhydrazones in high yields.
Investigation on the electrochemistry and cytotoxicity of the natural product marcanine A and its synthetic derivatives
2015, Jacobs, Nadine, Lang, Steffen, Panisch, Robin, Wittstock, Gunther, Groth, Ulrich, Nasiri, Hamid R.
The electrochemistry and cytotoxicity of marcanine A were investigated by electrochemical, computational and cellular studies. To enable a structure–toxicity-relationship of the natural product, eleven novel synthetic derivatives with different electrochemical properties were synthesized and tested. Derivative 5 revealed a GI50 in the low μM range, being more active than the actual natural product. A clear correlation was found between the experimental and the calculated data.
Trifluoromethylated Nucleosides : A Building Block Approach to Cytotoxic Adenosine Analogues
2014, Drexler, Johannes, Groth, Ulrich
Adenosine analogue nucleosides are a fundamental part of medicinal chemistry. Tubercidin is a well-known example, but its application is limited due to high toxicity. The development of less toxic synthetic analogues is therefore highly desirable. Here we show the synthesis of fluorinated nucleosides based on the pyrrolo[2,3-d]pyrimidine (7-deazapurine) motif. The synthetic approach is based on an easily accessible trifluoromethylated acetoacetate and several amidines, as building blocks. This allows for simultaneous introduction of a CF3 group as well as a variety of C2 substituents for the synthesis of the heterocyclic part, including alkyl, aryl, SMe, Cl, N3 and NH2 moieties. Glycosylation of the fully pre-functionalized heterocycles proceeds with excellent β-selectivity. Cytotoxicities were determined using an AlamarBlue assay with HeLa S3 and Hep G2 cancer cell lines. The effect of C2 substitution was explored and a lead structure candidate with IC50 values of 90 ± 49 nM (HeLa S3) and 28 ± 9 nM (Hep G2) was identified.
Microwave‐Assisted and Ultrasonic‐Assisted Three‐Component Heterocyclization of 4‐Amino‐5‐carboxamido‐1,2,3‐triazole, Thiopyran‐3‐one‐1,1‐dioxide, and Aromatic Aldehydes
2013-04-02, Gladkov, Eugene S., Desenko, Sergey M., Konovalova, Irina S., Groth, Ulrich, Shishkin, Oleg V., Vashchenko, Elena V., Chebanov, Valentin A.
Three‐component heterocyclization of 4‐amino‐5‐carboxamido‐1,2,3‐triazole, thiopyran‐3‐one‐1,1‐dioxide, and aromatic aldehydes under ultrasonic and microwave irradiation was studied. Regardless of the reaction parameters, 5,6,7,9‐tetrahydro‐4H‐thiopyrano[3,2‐d][1,2,3]triazolo[1,5‐a]pyrimidine‐8,8‐dioxides were isolated as sole reaction products whose structures were proven with help of NMR data and X‐ray analysis.