TY  - JOUR
A1  - Müller, Patrick
A1  - Meta, Mergim
A1  - Meidner, Jan Laurenz
A1  - Schwickert, Marvin
A1  - Meyr, Jessica
A1  - Schwickert, Kevin
A1  - Kersten, Christian
A1  - Zimmer, Collin
A1  - Hammerschmidt, Stefan Josef
A1  - Frey, Ariane
A1  - Lahu, Albin
A1  - de la Hoz-Rodríguez, Sergio
A1  - Agost-Beltrán, Laura
A1  - Rodríguez, Santiago
A1  - Diemer, Kira
A1  - Neumann, Wilhelm
A1  - Gonzàlez, Florenci V.
A1  - Engels, Bernd
A1  - Schirmeister, Tanja
T1  - Investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors — a comprehensive reactivity and selectivity study
JF  - International Journal of Molecular Sciences
N2  - Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences suited for five different proteases were investigated, highlighting the impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity. Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum mechanics simulations.
KW  - covalent inhibitors
KW  - in vitro study
KW  - protease inhibitors
KW  - peptidomimetic sequence
KW  - warhead
KW  - reactivity and selectivity study
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313596
SN  - 1422-0067
VL  - 24
IS  - 8
ER  - 
TY  - JOUR
A1  - Weiser, Jonas
A1  - Cui, Jingjing
A1  - Dewhurst, Rian D.
A1  - Braunschweig, Holger
A1  - Engels, Bernd
A1  - Fantuzzi, Felipe
T1  - Structure and bonding of proximity‐enforced main‐group dimers stabilized by a rigid naphthyridine diimine ligand
JF  - Journal of Computational Chemistry
N2  - The development of ligands capable of effectively stabilizing highly reactive main‐group species has led to the experimental realization of a variety of systems with fascinating properties. In this work, we computationally investigate the electronic, structural, energetic, and bonding features of proximity‐enforced group 13–15 homodimers stabilized by a rigid expanded pincer ligand based on the 1,8‐naphthyridine (napy) core. We show that the redox‐active naphthyridine diimine (NDI) ligand enables a wide variety of structural motifs and element‐element interaction modes, the latter ranging from isolated, element‐centered lone pairs (e.g., E = Si, Ge) to cases where through‐space π bonds (E = Pb), element‐element multiple bonds (E = P, As) and biradical ground states (E = N) are observed. Our results hint at the feasibility of NDI‐E2 species as viable synthetic targets, highlighting the versatility and potential applications of napy‐based ligands in main‐group chemistry.
KW  - bond theory
KW  - computational chemistry
KW  - density functional calculations
KW  - main group elements
KW  - N ligands
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312586
VL  - 44
IS  - 3
SP  - 456
EP  - 467
ER  - 
TY  - JOUR
A1  - Klein, Philipp
A1  - Barthels, Fabian
A1  - Johe, Patrick
A1  - Wagner, Annika
A1  - Tenzer, Stefan
A1  - Distler, Ute
A1  - Le, Thien Anh
A1  - Schmid, Paul
A1  - Engel, Volker
A1  - Engels, Bernd
A1  - Hellmich, Ute A.
A1  - Opatz, Till
A1  - Schirmeister, Tanja
T1  - Naphthoquinones as covalent reversible inhibitors of cysteine proteases — studies on inhibition mechanism and kinetics
JF  - Molecules
N2  - The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.
KW  - protease
KW  - rhodesain
KW  - covalent reversible inhibition
KW  - 1,4-naphthoquinone
KW  - nucleophilic addition
KW  - prodrug
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203791
SN  - 1420-3049
VL  - 25
IS  - 9
ER  - 
TY  - JOUR
A1  - Klein, Philipp
A1  - Johe, Patrick
A1  - Wagner, Annika
A1  - Jung, Sascha
A1  - Kühlborn, Jonas
A1  - Barthels, Fabian
A1  - Tenzer, Stefan
A1  - Distler, Ute
A1  - Waigel, Waldemar
A1  - Engels, Bernd
A1  - Hellmich, Ute A.
A1  - Opatz, Till
A1  - Schirmeister, Tanja
T1  - New cysteine protease inhibitors: electrophilic (het)arenes and unexpected prodrug identification for the Trypanosoma protease rhodesain
JF  - Molecules
N2  - Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the S\(_N\)Ar addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (K\(_i\) = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the S\(_N\)Ar reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation
KW  - cysteine protease
KW  - rhodesain
KW  - electrophilic (het)arene
KW  - nucleophilic aromatic substitution
KW  - Meisenheimer complex
KW  - π-complex
KW  - prodrug
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203380
SN  - 1420-3049
VL  - 25
IS  - 6
ER  - 
TY  - JOUR
A1  - Franzsico, Marcos A. S.
A1  - Fantuzzi, Felipe
A1  - Cardozo, Thiago M.
A1  - Esteves, Pierre M.
A1  - Engels, Bernd
A1  - Oliveira, Ricardo R.
T1  - Taming the Antiferromagnetic Beast: Computational Design of Ultrashort Mn-Mn Bonds Stabilized by N-Heterocyclic Carbenes
JF  - Chemistry—A European Journal
N2  - The development of complexes featuring low-valent, multiply bonded metal centers is an exciting field with several potential applications. In this work, we describe the design principles and extensive computational investigation of new organometallic platforms featuring the elusive manganese-manganese bond stabilized by experimentally realized N-heterocyclic carbenes (NHCs). By using DFT computations benchmarked against multireference calculations, as well as MO- and VB-based bonding analyses, we could disentangle the various electronic and structural effects contributing to the thermodynamic and kinetic stability, as well as the experimental feasibility, of the systems. In particular, we explored the nature of the metal-carbene interaction and the role of the ancillary η\(^{6}\) coordination to the generation of Mn\(_{2}\) systems featuring ultrashort metal-metal bonds, closed-shell singlet multiplicities, and positive adiabatic singlet-triplet gaps. Our analysis identifies two distinct classes of viable synthetic targets, whose electrostructural properties are thoroughly investigated.
KW  - metal-metal interactions
KW  - ab initio calculations
KW  - carbene ligands
KW  - density functional calculations
KW  - manganese
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256874
VL  - 27
IS  - 47
ER  - 
TY  - JOUR
A1  - Schmidt, Paul
A1  - Fantuzzi, Felipe
A1  - Klopf, Jonas
A1  - Schröder, Niklas B.
A1  - Dewhurst, Rian D.
A1  - Braunschweig, Holger
A1  - Engel, Volker
A1  - Engels, Bernd
T1  - Twisting versus delocalization in CAAC- and NHC-stabilized boron-based biradicals: the roles of sterics and electronics
JF  - Chemistry - A European Journal
N2  - Twisted boron-based biradicals featuring unsaturated C\(_2\)R\(_2\) (R=Et, Me) bridges and stabilization by cyclic (alkyl)(amino)carbenes (CAACs) were recently prepared. These species show remarkable geometrical and electronic differences with respect to their unbridged counterparts. Herein, a thorough computational investigation on the origin of their distinct electrostructural properties is performed. It is shown that steric effects are mostly responsible for the preference for twisted over planar structures. The ground-state multiplicity of the twisted structure is modulated by the σ framework of the bridge, and different R groups lead to distinct multiplicities. In line with the experimental data, a planar structure driven by delocalization effects is observed as global minimum for R=H. The synthetic elusiveness of C\(_2\)R\(_2\)-bridged systems featuring N-heterocyclic carbenes (NHCs) was also investigated. These results could contribute to the engineering of novel main group biradicals.
KW  - chemistry
KW  - radicals
KW  - ab initio calculations
KW  - boron
KW  - carbene ligands
KW  - density functional calculations
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256636
VL  - 27
IS  - 16
ER  - 
TY  - JOUR
A1  - Brückner, Tobias
A1  - Fantuzzi, Felipe
A1  - Stennett, Tom E.
A1  - Krummenacher, Ivo
A1  - Dewhurst, Rian D.
A1  - Engels, Bernd
A1  - Braunschweig, Holger
T1  - Isolation of neutral, mono-, and dicationic B\(_2\)P\(_2\) rings by diphosphorus addition to a boron-boron triple bond
JF  - Angewandte Chemie International Edition
N2  - The NHC-stabilised diboryne (B\(_2\)(SIDep)\(_2\); SIDep=1,3-bis(2,6-diethylphenyl)imidazolin-2-ylidene) undergoes a high-yielding P−P bond activation with tetraethyldiphosphine at room temperature to form a B\(_2\)P\(_2\) heterocycle via a diphosphoryldiborene by 1,2-diphosphination. The heterocycle can be oxidised to a radical cation and a dication, respectively, depending on the oxidant used and its counterion. Starting from the planar, neutral 1,3-bis(alkylidene)-1,3-diborata-2,4-diphosphoniocyclobutane, each oxidation step leads to decreased B−B distances and loss of planarity by cationisation. X-ray analyses in conjunction with DFT and CASSCF/NEVPT2 calculations reveal closed-shell singlet, butterfly-shaped structures for the NHC-stabilised dicationic B\(_2\)P\(_2\) rings, with their diradicaloid, planar-ring isomers lying close in energy.
KW  - inorganic chemistry
KW  - radicals
KW  - boron
KW  - density functional calculations
KW  - oxidation
KW  - phosphorus heterocycles
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256451
VL  - 60
IS  - 24
ER  - 
TY  - JOUR
A1  - Ramler, Jaqueline
A1  - Fantuzzi, Felipe
A1  - Geist, Felix
A1  - Hanft, Anna
A1  - Braunschweig, Holger
A1  - Engels, Bernd
A1  - Lichtenberg, Crispin
T1  - The dimethylbismuth cation: entry into dative Bi-Bi bonding and unconventional methyl exchange
JF  - Angewandte Chemie International Edition
N2  - The dimethyl bismuth cation, [BiMe\(_2\)(SbF\(_6\))], has been isolated and characterized. Reaction with BiMe\(_3\) allows access to the first compound featuring Bi→Bi donor–acceptor bonding. In solution, dynamic behavior with methyl exchange via an unusual S\(_E\)2 mechanism is observed, underlining the unique properties of bismuth species as soft Lewis acids with the ability to undergo reversible Bi−C bond cleavage.
KW  - inorganic chemistry
KW  - methyl exchange
KW  - bismuth
KW  - cationic species
KW  - electrophilic substitution
KW  - Lewis acidity
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256543
VL  - 60
ER  - 
TY  - JOUR
A1  - Mukhopadhyay, Deb Pratim
A1  - Schleier, Domenik
A1  - Wirsing, Sara
A1  - Ramler, Jaqueline
A1  - Kaiser, Dustin
A1  - Reusch, Engelbert
A1  - Hemberger, Patrick
A1  - Preitschopf, Tobias
A1  - Krummenacher, Ivo
A1  - Engels, Bernd
A1  - Fischer, Ingo
A1  - Lichtenberg, Crispin
T1  - Methylbismuth: an organometallic bismuthinidene biradical
JF  - Chemical Science
N2  - We report the generation, spectroscopic characterization, and computational analysis of the first free (non-stabilized) organometallic bismuthinidene, BiMe. The title compound was generated in situ from BiMe\(_3\) by controlled homolytic Bi–C bond cleavage in the gas phase. Its electronic structure was characterized by a combination of photoion mass-selected threshold photoelectron spectroscopy and DFT as well as multi-reference computations. A triplet ground state was identified and an ionization energy (IE) of 7.88 eV was experimentally determined. Methyl abstraction from BiMe\(_3\) to give [BiMe(_2\)]• is a key step in the generation of BiMe. We reaveal a bond dissociation energy of 210 ± 7 kJ mol\(^{−1}\), which is substantially higher than the previously accepted value. Nevertheless, the homolytic cleavage of Me–BiMe\(_2\) bonds could be achieved at moderate temperatures (60–120 °C) in the condensed phase, suggesting that [BiMe\(_2\)]• and BiMe are accessible as reactive intermediates under these conditions.
KW  - methylbismuth
KW  - Photoelektronenspektroskopie
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251657
UR  - https://pubs.rsc.org/en/content/articlelanding/2020/SC/D0SC02410D
VL  - 11
IS  - 29
ER  - 
TY  - JOUR
A1  - Rang, Maximilian
A1  - Fantuzzi, Felipe
A1  - Arrowsmith, Merle
A1  - Krummenacher, Ivo
A1  - Beck, Eva
A1  - Witte, Robert
A1  - Matler, Alexander
A1  - Rempel, Anna
A1  - Bischof, Tobias
A1  - Radacki, Krzysztof
A1  - Engels, Bernd
A1  - Braunschweig, Holger
T1  - Reduktion und Umlagerung eines Bor(I)‐Carbonylkomplexes
JF  - Angewandte Chemie
N2  - Bei der Einelektronenreduktion eines durch eine cyclisches (Alkyl)(amino)carben (CAAC) stabilisierten Arylborylen-Carbonylkomplexes erfolgt die Bildung eines dimeren Borylketyl-Radikalanions, bedingt durch eine intramolekulare Arylmigration zum CO Kohlenstoffatom. Computergestützte Analyse liefert Hinweise auf eine radikalanionische [(CAAC)B(CO)Ar]\(^{.-}\) Zwischenstufe. Weiterführende Reduktion des entstandenen Komplexes liefert ein hoch nukleophiles (Boranyliden)methanolat.
KW  - Biradikale
KW  - Bor-Carbonylkomplexe
KW  - Dichtefunktionalrechnungen
KW  - Reduktionen
KW  - Umlagerungen
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224409
VL  - 133
IS  - 6
SP  - 3000
EP  - 3005
ER  -