C. Bäuerlein, A. Geyer. Synthesis of Fusahexin and characterization of a natural b-turn dipeptide. in print. 2025, pages.

E. Al-Masri, A. M. Shuaib, M. Al-Refai, B. F. Ali, L. Salah, C. S. Ponseca, N. Aljaar, A. Geyer. Fluorescence properties of pyridine and pyridine-carbonitrile derivatives: Photophysical and structural analysis. J. Mol. Struct. 2025, 1343, 142857.

DOI: 10.1016/j.molstruc.2025.142857

T. Zimmer, S. I. Ivlev, A. Geyer. Synthesis of β,β-dinaphthyl amino acids: towards molecular gearing in peptides and mini-proteins. Chem. Eur. J. 2025, pages.

C. Noelker, F. Seitz, A. Sturn, F. Neff, L.-C. Andrei-Selmer, L. Rau, A. Geyer, J. A. Ross, M. Bacher, R. Dodel. Autoantibodies against α-synuclein inhibit its aggregation and cytotoxicity. J. Autoimmunity, 2025, 152, 103390.

DOI: 10.1016/j.jaut.2025.103390

B. F. Ali, M. Al-Refai, E. Al-Masri, A. Shtaiwi, N. Aljaar, A. Geyer, S. I. Ivlev. Two isomorphous series of 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(aryl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one derivatives: X-ray structures, intermolecular interactions, Hirshfeld analysis and molecular docking. J. Mol. Struct. 2024, 1302, 137395.

DOI: 10.1016/j.molstruc.2023.136356

T. Zimmer, A. Geyer. Synthesis and conformational analysis of b,b,-Diaryl-a-amino acids: on the way to molecular gearing. J. Pep. Sci. 2024, ID: 616-P2.003, 263-264.

C. Bäuerlein, A. Geyer. Synthesis of the natural peptide product Fusahexin. J. Pep. Sci. 2024, ID: 531-P1.047, 102-103.

F. Kozak, D. Brandis, C. Pötzl, L. M. Epasto, D. Reichinger, A. Polyansky, B. Zagrovic, F. Daus. A. Geyer, C. Becker, D. Kurzbach. An atomistic view on the mechanism of diatom peptide-guided biomimetic silica formation. J. Pep. Sci. 2024, ID: 507-P1.299, 246.

F. Kozak, D. Brandis, C. Pötzl, L. M. Epasto, D. Reichinger, D. Obrist, H. Peterlik, A. Polyansky, B. Zagrovic, F. Daus, A. Geyer, C.F.W. Becker, D. Kurzbach. An atomistic view on the mechanism of diatom peptide-guided biomimetic silica formation. Adv. Sci. 2024, 11, 2401239.

DOI: 10.1002/advs. 202401239

M. Al-Refai, B. F. Ali, E. Al-Masri, N. Aljaar, A. Geyer, L. Salah, A. Shuaib. Blue-emitting monochlorothiophenyl-pyridine-carbonitriles: Synthesis, structural analysis, and fluorescence properties. J. Mol. Struct. 2023, 1294, 136356.

DOI. 10.1016/j.molstruc.2023.136356

M. Al-Refai, B. F. Ali, E. K. Al-Masri, I. A. Mansi, N. Aljaar, B. Abu-Irmaileh, A. Geyer, S. I. Ivlev. Synthesis, characterization, antibacterial activity and cytotoxicity of (1′R,2′S,7a′S)‐2′‐(2,5‐dichlorothiophene‐3‐carbonyl)‐1′‐(aryl)‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizin]‐2‐one derivatives. 

J. Heterocyclic Chem. 2023, 60, 2009-2022.

DOI: 10.1002/jhet.4732

E. Al-Masri, M. Al-Refai, H. T. Al-Masri, B. F. Ali, S. Makhseed, L. Salah, B. Ghazal, A. Geyer, S. I. Ivlev, M. Abu-Sini. Synthesis, characterization, crystal structure, and fluorescence behavior of new 4-aryl-6-(2,5-dichlorothiophen-3-yl)-2-methylpyridine-3-carbonitrile derivatives. J. Mol. Struct. 2023, 1271, 134034-134049.

DOI: 10.1016/j.molstruc.2022.134034

Incorporation of Indoylated Phenylalanine Yields a Sub-Micromolar Selective Melanocortin-4 Receptor Antagonist Tetrapeptide. 

M. Ericson, C. Larson, K. Freemann, L. Nicke, A. Geyer, C. Haskell-Luevano. ACS Omega, 2022, in print

Manuscript ID: ao-2022-03307d.R1 

Abstract 

The silica mineralisation properties of synthetic Silaffin-1A1 (synSil‑1A1). 

Fabian Daus, Xiulan Xie, Armin Geyer. Org. Biomol. Chem., 2022, 20, 3387-3396. 

DOI: 10.1039/D2OB00390B

Supplementary Information

Abstract The synthetic monodisperse pentadecapeptide synSil-1A1 is a representative of the microdisperse mixture of the native silaffin natSil-1A1 produced by the diatom Cylindrotheca fusiformis. The octaphosphorylated zwitterionic synSil-1A1 is able to mineralise silica under slightly acidic conditions at pH 5.5, which is the physiologically relevant pH range assumed. Like the posttranslational modifications of the native silaffins, synSil-1A1 is functionalised on all four lysine and phosphorylated on all seven serine residues. We describe the synthesis of a trimethyl-δ-hydroxy-L-lysine building block, the incorporation of this choline-type amino acid in peptide synthesis and its phosphorylation, together with all further posttranslational modifications observed in the native silaffins. Quantitative structure–activity relationships from silicification experiments at high dilution reveal the unique mineralisation properties of the hyperphosphorylated peptide as a single substance and in interaction with long-chain polyamines (LCPA). Diffusion-ordered spectroscopy (DOSY) experiments reveal the formation of polyelectrolyte complexes (PEC) between synSil-1A1 and long-chain polyamines, which promotes the silicification process. The microdroplets have an overall balanced ratio of 100–150 cationic and the same number of anionic charges. The unique zwitterionic synSil-1A1 confirms the prevailing molecular model of biosilicification and validates it with quantitative data based on a single phosphopeptide species, avoiding the usual unphysiologically high concentrations of phosphate of many previous in vitro silicification experiments.

 (no graphical abstract available)

Crystal structure and supramolecularity of (E)-4-(4-tert-butylphenyl)but-3-en-2-one. 

Eman Al-Masri, Mahmoud Al-Refai, Harbi Tomah Al-Masri, Armin Geyer, Sergei I. Ivlev, Basem F. Ali. Jordan Journal of Chemistry 2021, Vol. 16, No. 3, 99-104.

DOI: 10.47014/16.3.1

Synthesis, characterization, antibacterial and cytotoxic evaluation of new 6-(chlorothiophenyl)-2-(2-oxopropoxy)pyridine-3-carbonitrile derivatives and their corresponding furo[2,3-b]pyridines derivatives.

Ala’a B. Said, Mahmoud Al-Refai, Armin Geyer, Iman A. Mansi, Basem Fares Ali. Heterocycles 2021, Vol. 102, No. 11, 2153-2167.

DOI: 10.3987/com-21-14534

Abstract The synthesis of a new series of 6-(chlorothiophenyl)-2-(2-oxopropoxy)pyridine-3-carbonitrile compounds 2 and 5 and their furo[2,3-b]pyridines bearing heteroaryl substituents 3 and 6 in high yield is reported. The 6-(chlorothiophenyl)-2-(2-oxopropoxy)pyridine-3-carbonitrile derivatives (2a-f) and (5a-d) were prepared from the corresponding 3-cyano-(2H)-pyridones (1a-f) and (4a-d) followed by the Thorpe-Ziegler ring cyclization in the presence of sodium methoxide to give the target furo[2,3-b]pyridine derivatives (3a-f) and (6a-d). Proposed structures of the new compounds are based on NMR and mass spectral data. Antibacterial evaluation of (2a-d), (2f), (5a-d), (3a-d), (3f), and (6a-d) derivatives against eight different microorganisms shows no activity towards any of the tested bacteria while compounds (6a) and (6c) showed weak antibacterial activity with inhibition zone of 10 mm. Cytotoxic assessment against MCF7 breast cancer cells reveals that 10 of the derivatives were found to decrease cell viability in a dose dependent manner at concentration of 100 μM, but six of them decreased it to less than 50% and had IC50’s ranging from 23.3 to 41.2 μM.

High five! Methyl probes at five ring positions of phenylalanine explore the hydrophobic core dynamics of zinc finger miniproteins.

Philip Horx, Armin Geyer. Chem. Sci. 2021, 12, 11455-11463.

DOI: 10.1039/d1sc02346b

Supporting Information

Abstract The elucidation of internal dynamics in proteins is essential for the understanding of their stability and functionality. Breaking the symmetry of the degenerate rotation of the phenyl side chain provides additional structural information and allows a detailed description of the dynamics. Based on this concept, we propose a combination of synthetic and computational methods, to study the rotational mobility of the Phe ring in a sensitive zinc finger motif. The systematic methyl hopping around the phenylalanine ring yields o-, m-, p-tolyl and xylyl side chains that provide a vast array of additional NOE contacts, allowing the precise determination of the orientation of the aromatic ring. MD simulations and metadynamics complement these findings and facilitate the generation of free energy profiles for each derivative. Previous studies used a wide temperature window in combination with NMR spectroscopy to elucidate the side chain mobility of stable proteins. The zinc finger moiety exhibits a limited thermodynamic stability in a temperature range of only 40 K, making this approach impractical for this compound class. Therefore, we have developed a method that can be applied even to thermolabile systems and facilitates the detailed investigation of protein dynamics. 

Covalent linkage and macrocyclization preserve and enhance synergistic interactions in catalytic amyloids. 

Zsofia Lengyel-Zhand, Liam R. Marshall, Maximilian Jung, Megha Jayachandran, Min-Chul Kim, Austin Kriews, Ola V. Makhlynets, H. Christopher Fry, Armin Geyer, Ivan V. Korendovych. ChemBioChem 2021, 22, 585-591. 

DOI:10.1002/cbic.202000645

Supporting Informtion

Abstract How might complexity arise from short peptides? Synergistic interactions between the side chains of catalytic amyloids are locked into place by linkers between the peptides, and these new designs result in faster assembly and asymmetric assemblies. These could serve as a potential link in the evolutionary path between abiotic peptides and complex enzymes.

Tryptophan analogues with fixed side-chain orientation: expanding the scope. 

Lennart Nicke, Philip Horx, Ronny Müller, Sylvia Els-Heindl, Armin Geyer. ChemBioChem, 2021, 22, 330-335.

DOI: 10.1002/cbic.202000424

Supporting Information

Abstract A generalized synthetic strategy is proposed here for the synthesis of asymmetric β-indoylated amino acids by 8-aminoquinoline (8AQ)-directed C(sp3)-H functionalization of suitably protected precursors. Peptides containing one of the four stereoisomers of (indol-3-yl)-3-phenylalanine at position 2 of the parent peptide KwFwLL-NH2 (w=d-Trp) cover a wide range of activities as ghrelin receptor inverse agonists, among them the most active described until now. This application exemplarily shows how β-indoylated amino acids can be used for the systematic variation of the position of an indole group in a bioactive peptide.

Interactions of long-chain polyamines with silica studied by molecular dynamics simulations and solid-state NMR spectroscopy. 

Maria Montagna, Stephan Ingmar Brückner, Arezoo Dianat, Rafael Gutierrez, Fabian Daus, Armin Geyer, Eike Brunner, Gianaurelio Cuniberti. Langmuir 2020, 36, 11600-11609.

DOI: 10.1021/acs.langmuir.0c02157

Supporting Information

Abstract The investigation of molecular interactions between silica phases and organic components is crucial for elucidating the main steps involved in the biosilica mineralization process. In this respect, the structural characterization of the organic/inorganic interface is particularly useful for a deeper understanding of the dominant mechanisms of biomineralization. In this work, we have investigated the interaction of selectively 13C- and 15N-labeled atoms of organic long-chain polyamines (LCPAs) with 29Si-labeled atoms of a silica layer at the molecular level. In particular, silica/LCPA nanocomposites were analyzed by solid-state NMR spectroscopy in combination with all-atom molecular dynamics simulations. Solid-state NMR experiments allow the determination of 29Si–15N and 29Si–13C internuclear distances, providing the parameters for direct verification of atomistic simulations. Our results elucidate the relevant molecular conformations as well as the nature of the interaction between the LCPA and a silica substrate. Specifically, distances and second moments suggest a picture compatible with (i) LCPA completely embedded in the silica phase and (ii) the charged amino groups located in close vicinity of silanol groups.

(No graphical abstract available)

MON-185 ACTH-derived peptide antagonists as an alternative treatment strategy for congenital adrenal hyperplasia. 

J. Endocrin. Soc. 2020, 4, A298-A299. Tina Schubert, Lennart Nicke, André Schanze, Nicole Reisch, Armin Geyer, Katrin Koehler, Angela Huebner.

DOI: 10.1210/jendso/bvaa046.589

Abstract Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by different enzyme deficiencies in the steroid hormone synthesis leading to a disturbed cortisol biosynthesis. The medical treatment of CAH includes suboptimal ACTH-suppressing high glucocorticoid doses to reduce adrenal hyperplasia and overproduction of androgens. These inappropriate corticoid substitutions are often associated with undesirable side effects such as arterial hypertension, growth failure and obesity. Since the current therapy of patients with CAH is often unsatisfactory, innovative treatment options are required.

The aim of our study was to specifically block the melanocortin 2 receptor (MC2R) signaling pathway as an alternative treatment strategy for CAH. We tested ACTH-derived selective peptides with incorporation of various synthetic non-natural amino acids in the activation motif of ACTH. To study the antagonistic activity of the peptides, cAMP production of MC2R/MRAP stably transfected human embryonic kidney (HEK) 293 cells were measured. All new synthesized peptide antagonists reduced ACTH-stimulated MC2R activity as competitive inhibitors indicated by a reduced in vitro cAMP response. Cells pre-incubated with peptide LNP009 showed the most efficient blockade of the MC2R and the highest shift of EC50 of ACTH (33.8 nM ± 0.08 vs. 7.3 nM ± 0.09). LNP009 was additionally tested for specificity concerning the other known melanocortin receptors and showed no antagonistic effect up to 1 μM on MC3, MC4 or MC5 receptor transiently transfected HEK 293 cells. To further investigate the inhibitory effect of our most potent antagonist peptide LNP009 on the steroid hormone response, we assessed steroidogenic enzyme expression of the human adrenocortical tumor cell line NCI-H295RA and performed mass spectrometry analyzes of steroids in the cell culture supernatant. Pre-incubation with LNP009 reduced the expression of the genes CYP21A2, CYP11B1 and HSD3B2 in NCI-H295RA cells and significantly reduced the synthesis of aldosterone (P=0.046; n=3), cortisol (P=0.020; n=3) and corticosterone (P=0.035; n=3).

With the successful blocking of the ACTH binding and signal transduction by our antagonistic peptides, we anticipate an alternative approach for optimizing the treatment of CAH patients lacking the side effects of the currently used ACTH-suppressing corticoid therapy.

Phosphate-silica interactions in diatom biosilica and synthetic composites studied by rotational echo double resonance (redor) nmr spectroscopy.

Langmuir 2020, 36, 4332-4338.Felicitas Kolbe, Fabian Daus, Armin Geyer, Eike Brunner. 

DOI: 10.1021/acs.langmuir.0c00336

Supporting information

Abstract Biosilica is a biogenic composite material produced by organisms like diatoms. Various biomolecules are tightly attached or incorporated into biosilica. Examples are special proteins termed silaffins and long-chain polyamines (LCPAs). Presumably, these biomolecules are involved in the biosilica formation process. Silaffins are highly phosphorylated zwitterions with LCPAs post-translationally attached to lysine residues. In the present work, we use distance-dependent solid-state NMR experiments, especially the 31P{29Si} Rotational Echo Double Resonance (REDOR) technique, to study the environment of phosphate moieties in biosilica and in vitro synthesized SiO2-based composites. In contrast to the heterogeneous mixtures of biomolecules found in native biosilica, the described in vitro silicification experiments make use of a single synthetic phosphopeptide and an LCPA of well-defined and uniform structure. The heteronuclear correlations measured from these silica composites provide reliable 31P–29Si dipolar second moments and information about the distribution of the phosphopeptide within the silica material. The calculated second moment indicates close contact between phosphopeptides and silica. The phosphopeptides are incorporated into the silica composite in a disperse manner. Moreover, the REDOR data acquired for diatom biosilica also imply that phosphate groups are part of the silica–organic interface in this material.

Defining the mobility range of a hinge-type connection using molecular dynamics and metadynamics

Plos One 2020 15(4):e0230962 Philip Horx, Armin Geyer

DOI:10.1371/journal.pone.0230962

Supporting Information

Abstract A designed disulfide-rich β-hairpin peptide that dimerizes spontaneously served as a hinge-type connection between proteins. Here, we analyze the range of dynamics of this hinge dimer with the aim of proposing new applications for the DNA-encodable peptide and establishing guidelines for the computational analysis of other disulfide hinges. A recent structural analysis based on nuclear magnetic resonance spectroscopy and ion mobility spectrometry revealed an averaged conformation in the hinge region which motivated us to investigate the dynamic behavior using a combination of molecular dynamics simulation, metadynamics and free energy surface analysis to characterize the conformational space available to the hinge. Principal component analysis uncovered two slow modes of the peptide, namely, the opening and closing motion and twisting of the two β-hairpins assembling the hinge. Applying a collective variable (CV) that mimics the first dominating mode, led to a major expansion of the conformational space. The description of the dynamics could be achieved by analysis of the opening angle and the twisting of the β-hairpins and, thus, offers a methodology that can also be transferred to other derivatives. It has been demonstrated that the hinge peptide’s lowest energy conformation consists of a large opening angle and strong twist but is separated by small energy barriers and can, thus, adopt a closed and untwisted structure. With the aim of proposing further applications for the hinge peptide, we simulated its behavior in the sterically congested environment of a four-helix bundle. Preliminary investigations show that one helix is pushed out and a three-helix bundle forms. The insights gained into the dynamics of the tetra-disulfide peptide and analytical guidelines developed in this study may contribute to the understanding of the structure and function of more complex hinge-type proteins, such as the IgG antibody family.

Comparing the hinge-type mobility of natural and designed intermolecular bi-disulfide domains

Front. Chem. 2020, 8, 25 Philip Horx, Armin Geyer

DOI: 10.3389/fchem.2020.00025

Supporting Information

Abstract A pair of intermolecular disulfide bonds connecting two protein domains restricts their relative mobility in a systematic way. The bi-disulfide hinge cannot rotate like a single intermolecular disulfide bond yet is less restrained than three or more intermolecular disulfides which restrict the relative motion to a minimum. The intermediate mobility of bi-disulfide linked domains is characterized by their dominating opening and closing modes comparable to the mechanics of a door hinge on the macroscopic scale. Here we compare the central hinge region of Immunoglobulin G1 (IgG1) which is highly conserved among different species, with a recently designed hinge-type motif CHWECRGCRLVC from our lab, that was successfully used for the dimerization of the IgG1/κ-ab CL4 monocolonal antibody (mab). The minimal length of these synthetic hinges comprises only 12 amino acids, rendering them ideal models for computational studies. Well-tempered metadynamics was performed to adequately describe the available conformational space defined by the different hinges. In spite of the differences in amino acid composition and ring sizes, there are characteristic similarities of designed and natural hinges like the dependent mobility of the individual strands of each hinge domain.

The role of phosphopeptides in the biomineralization of silica

Org. Biomol. Chem. 2020, 18, 700-706 Fabian Daus, Erik Pfeifer, Kevin Seipp, Norbert Hampp, Armin Geyer

DOI: 10.1039/c9ob02438g

Supporting Information

Abstract We investigated the silicification activity of hyperphosphorylated peptides in combination with long-chain polyamines (LCPA). The bioinspired in vitro silicification experiments with peptides containing different amounts of phosphorylated serines showed structure–activity dependence by altering the amount and morphology of the silica precipitate. Our study provides an explanation for the considerable metabolic role of diatoms in the synthesis of hyperphosphorylated poly-cationic peptides such as natSil-1A1. The efficient late-stage phosphorylation of peptides yielded a synthetic heptaphosphopeptide whose silicification properties resemble those of natSil-1A1. As opposed to this, unphosphorylated poly-cationic peptides or LCPA require concentrations above 1 mM for silicification. Hyperphosphorylated peptides showed a linear dependence between the amount of dissolved peptides and the amount of precipitated silica in the concentration range below 1 mM. Under mildly acidic conditions and short precipitation times, the concentration of the added LCPA determined the size of the silica spheres.

The synthesis, characterization, cytotoxic activity assessment and structure–activity relationship of 4-aryl-6-(2,5-dichlorothiophen-3-yl)-2-methoxypyridine-3-carbonitriles

Molecules 2019, 24, 4072-4083 Mahmoud Al-Refai, Mohammad M. Ibrahim, Mohamad Nurul Azmi, Hasnah Osman, Mohamad Hafizi Abu Bakar, Armin Geyer

DOI: 10.3390/molecules24224072

Supplementary Material

Abstract A series of 2-methoxypyridine-3-carbonitrile (5a–i)-bearing aryl substituents were successfully synthesized in good yields by the condensation of chalcones (4a–i) with malononitrile in basic medium. The condensation process, in most cases, offers a route to a variety of methoxypyridine derivatives (6a–g) as side products in poor yields. All new compounds were fully characterized using different spectroscopic methods. Mass ESI-HMRS measurements were also performed. Furthermore, these compounds were screened for their in vitro cytotoxicity activities against three cancer cell lines; namely, those of the liver (line HepG2), prostate (line DU145) and breast (line MBA-MB-231). The cytotoxicity assessment revealed that compounds 5d, 5g, 5h and 5i exhibit promising antiproliferative effects (IC50 1–5 µM) against those three cancer cell lines.

Reversible covalent end-capping of collagen model peptides

Chem. Eur. J. 2019, 25, 14278-14283 Christoph Priem, Armin Geyer

DOI: org/10.1002/chem.201903460

Supporting Information

Abstract The combination of supramolecular aggregation of collagen model peptides with reversible covalent end‐capping of the formed triple helix in a single experimental set‐up yielded minicollagens, which were characterized by a single melting temperature. In spite of the numerous possible reaction intermediates, a specific synthetic collagen with a leading, middle and trailing strand is formed in a highly cooperative self‐assembly process.

Directed C(sp3)−H arylation of tryptophan: transformation of the directing group into an activated amide 

Chem. Sci. 2019, 10, 8634-8641. Lennart Nicke, Philip Horx, Klaus Harms, Armin Geyer

DOI: 10.1039/c9sc03440d

Supporting Information

Abstract The he 8-aminoquinoline (8AQ) directed C(sp3)–H functionalization was applied in the synthesis of β-arylated tryptophan derivatives. The laborious protecting group reorganization towards α-amino acids compatible for solid phase peptide synthesis (SPPS) was cut short by the transformation of the directing group into an activated amide, which was either used directly in peptide coupling or in the gram scale synthesis of storable Fmoc-protected amino acids for SPPS. In this work, directed C–H activation and nonplanar amide chemistry complement each other for the synthesis of hybrids between phenylalanine and tryptophan with restricted side chain mobility.

Side chain orientation of tryptophan analogs determines agonism and inverse agonism in short ghrelin peptides

ChemMedChem 2019, 14, 1849-1855. Lennart Nicke, Ronny Müller, Armin Geyer, Sylvia Els‐Heindl

DOI: 10.1002/cmdc.201900409

Supporting Information

Abstract We describe two synthetic amino acids with inverted side chain stereochemistry, which induce opposite biological activity. Phe4 is an important part of the activation motif of ghrelin, and in short peptide inverse agonists such as KwFwLL‐NH2, the aromatic core is necessary for inactivation of the receptor. To restrict indole/phenyl mobility and simultaneously strengthen the interaction between peptide and receptor, we exchanged the natural monoaryl amino acids for diaryl amino acids derived from tryptophan. By standard solid‐phase peptide synthesis, each of them was inserted into ghrelin or in the aromatic core of the inverse agonist. Both ghrelin analogues showed nanomolar activity, indicating sufficient space to accommodate the additional side chain. In contrast, diaryl amino acids in the inverse agonist had considerable influence on receptor signaling. Whereas the introduction of Wsf maintains inverse agonism of the peptide, Wrf shifts the receptor more to active states and can induce agonism depending on its introduction site.

Synthesis, characterization, crystal structure and supramolecularity of ethyl (E)-2-cyano-3-(3-methylthiophen-2-yl)acrylate and a new polymorph of ethyl (E)-2-cyano-3-(thiophen-2-yl)acrylate

Acta Cryst. 2019, E75, 1357-1361. Mahmoud Al-Refai, Basem F. Ali, Ala´a B. Said, Armin Geyer, Michael Marsch, Klaus Harms

DOI: 10.1107/S2056989019011435

Supporting Information

Abstract The synthesis, crystal structure and structural motif of two thio­phene-based cyano­acrylate derivatives, namely, ethyl (E)-2-cyano-3-(3-methyl­thio­phen-2-yl)acrylate (1), C11H11NO2S, and ethyl (E)-2-cyano-3-(thio­phen-2-yl)acrylate (2), C10H9NO2S, are reported. Derivative 1 crystallized with two independent molecules in the asymmetric unit, and derivative 2 represents a new monoclinic (C2/m) polymorph. The mol­ecular conformations of 1 and the two polymorphs of 2 are very similar, as all non-H atoms are planar except for the methyl of the ethyl groups. The inter­molecular inter­actions and crystal packing of 1 and 2 are described and compared with that of the reported monoclinic (C2/m) polymorph of derivative 2 [Castro Agudelo et al. (2017). Acta Cryst. E73, 1287–1289].

3-(2,5-dichlorothiophen-3-yl)-5-(2,4-dimethoxyphenyl)-1-methyl-4,5-dihydro-1H-pyrazole.

IUCrData 2019, 4, x191046.  Mohammad M. Ibrahim, Mahmoud Al-Refai, Basem F. Ali, Armin Geyer, Klaus Harms, Michael Marsch

DOI: org/10.1107/S2414314619010460

Supporting Information

Abstract In the title compound, C16H16Cl2N2O2S, the pyrazole ring has an envelope conformation with the C atom bearing the phenyl ring being the flap. The dihedral angles between the central pyrazole ring (all atoms) and pendant thio­phene and phenyl rings are 2.00 (14) and 81.49 (12)°, respectively. In the crystal, weak C—HO, Clπ and π–π stacking inter­actions link the mol­ecules into a three-dimensional network.

Synthesis, characterization and cytotoxicity of new nicotinonitriles and their furo[2,3-b]pyridine derivatives.

J. Iran. Chem. Soc. 2019, 16, 715-722. Mohammad M. Ibrahim, Mahmoud Al-Refai, Mohamad Nurul Azmi, Hasnah Osman, Mohamad Hafizi Abu Bakar, Armin Geyer

DOI: org/10.1007/s13738-018-1549-y

Supporting Information

Abstract The present research work describes the synthesis of new series of nicotinonitrile (2) and furo[2,3-b]pyridine (3) heterocycles bearing thiophene substituent. The nicotinonitrile derivatives were prepared from the corresponding 3-cyano-(2H)-pyridones (1a–f) in excellent yields. The ring cyclization of the nicotinonitrile derivatives (2a–f) in the presence of sodium methoxide provided the furo[2,3-b]pyridines (3a–f) in moderate to good yields. All the newly synthesized compounds were characterized by extensive NMR analysis data, including 1D-NMR experiments (1H and 13C) and 2D-NMR experiments (COSY, HMBC, HSQC), as well as HRESIMS data. All the final products were subjected for cytotoxic activity against five different tumour cell lines including HeLa (cervical), DU145 (prostate), HepG2 (liver), MDA-MB-231 (breast-ER negative) and MCF7 (breast-ER positive), in addition to HSF1184 (normal human fibroblast) using the MTT assay. Compounds 2d and 3e were found to exhibit promising cytotoxicity with IC50 of < 20 µM against all different tested tumour cell lines. In addition, these compounds showed high selectivity (40–287 folds) for tumour cells over normal cells.

Diamondoid Amino Acid-based Peptide Kinase A Inhibitors

ChemMedChem 2019, 14, 663-672. Janis Müller, Romina A. Kirschner, Jan‐Philipp Berndt, Tobias Wulsdorf, Alexander Metz, Radim Hrdina, Peter R. Schreiner, Armin Geyer, Gerhard Klebe

DOI: 10.1002/cmdc.201800779

Supporting Information

Abstract The incorporation of diamondoid amino acids (DAAs) into peptide‐like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA‐containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid‐phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids. Affinity and binding pose are largely conserved. One variant showed 6.5‐fold potency improvement, most likely related to its increased side chain lipophilicity. A second variant exhibited slightly decreased affinity presumably due to loss of hydrogen‐bond contacts to surrounding water molecules of the first solvation shell.

Conceptional design of self-assembling bisubstrate-like inhibitors of protein kinase a resulting in a boronic acid glutamate linkage

ACS Omega 2019, 4, 775-784. Janis Müller, Romina A. Kirschner, Armin Geyer, Gerhard Klebe

DOI: 10.1021/acsomega.8b02364

Supporting Information

Abstract The spontaneous esterification of boronic acids with polyols provides a promising opportunity to generate self-assembled bisubstrate-like inhibitors within the binding pocket of cAMP-dependent protein kinase (PKA). As a first substrate component, we designed amino acids, which have either a boronic acid or ribopyranose side chain and introduced them to the substrate-like peptide protein kinase inhibitor (PKI). The second component was derived from the active-site inhibitor Fasudil, which was functionalized with phenylboronic acid. NMR spectroscopy in dimethylsulfoxide proved spontaneous reversible condensation of both components. Reinforced by the protein environment, both separately bound substrates were expected to react via boronic-ester formation bridging the two binding sites of PKA. Multiple crystal structures of PKA with bound PKIs, positionally modified with residues such as a ribopyranosylated serine and threonine or a phenylboronic acid attached to lysine via amide bonds, were determined with the phenylboronic acid-linked Fasudil. Although PKA accepts both inhibitors simultaneously, the expected covalent attachment between both components was not observed. Instead, spontaneous reaction of the terminal boronic acid group of the modified Fasudil with the carboxylate of Glu127 was detected once the latter residue is set free from a strong salt bridge formed with arginine by the original peptide inhibitor PKI. Thus, the desired self-assembly reaction occurs spontaneously in the protein environment by an unexpected carboxylic acid boronate complex. To succeed with our planned self-assembly reaction between both substrate components, we have to redesign the required reaction partners more carefully to finally yield the desired bisubstrate-like inhibitors in the protein environment.