An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4. Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4. The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Moreover, topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Thus, rationally designed EPI-X4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted

Competitive solvent-molecule interactions govern primary processes of diphenylcarbene in solvent mixtures

Photochemical reactions in solution often proceed via competing reaction pathways comprising intermediates that capture a solvent molecule. A disclosure of the underlying reaction mechanisms is challenging due to the rapid nature of these processes and the intricate identification of how many solvent molecules are involved. Here combining broadband femtosecond transient absorption and quantum mechanics/molecular mechanics simulations, we show for one of the most reactive species, diphenylcarbene, that the decision-maker is not the nearest solvent molecule but its neighbour. The hydrogen bonding dynamics determine which reaction channels are accessible in binary solvent mixtures at room temperature. In-depth analysis of the amount of nascent intermediates corroborates the importance of a hydrogen-bonded complex with a protic solvent molecule, in striking analogy to complexes found at cryogenic temperatures. Our results show that adjacent solvent molecules take the role of key abettors rather than bystanders for the fate of the reactive intermediate

Competitive solvent-molecule interactions govern primary processes of diphenylcarbene in solvent mixtures

Photochemical reactions in solution often proceed via competing reaction pathways comprising intermediates that capture a solvent molecule. A disclosure of the underlying reaction mechanisms is challenging due to the rapid nature of these processes and the intricate identification of how many solvent molecules are involved. Here combining broadband femtosecond transient absorption and quantum mechanics/molecular mechanics simulations, we show for one of the most reactive species, diphenylcarbene, that the decision-maker is not the nearest solvent molecule but its neighbour. The hydrogen bonding dynamics determine which reaction channels are accessible in binary solvent mixtures at room temperature. In-depth analysis of the amount of nascent intermediates corroborates the importance of a hydrogen-bonded complex with a protic solvent molecule, in striking analogy to complexes found at cryogenic temperatures. Our results show that adjacent solvent molecules take the role of key abettors rather than bystanders for the fate of the reactive intermediate

Pursuing primary processes of diphenylcarbene in binary solvent mixtures

An intermediate H-bonded complex formed in MeOH/MeCN solvent mixtures between photogenerated diphenylcarbene and a MeOH molecule is identified, both in theory and experiment. The complex is the ultrafast analog of findings at cryogenic temperatures

The Interaction Modes of Haloimidazolium Salts in Solution

We performed a comparative study on the interaction modes of 2‐haloimidazolium salts with anions in solution, particularly with regard to halogen bonding, hydrogen bonding and anion–π interactions. The syntheses and solid‐state analyses of a series of sterically and electronically modified 2‐haloimidazolium structures are presented. Detailed isothermal titration calorimetry (ITC) measurements, quantum mechanics/molecular mechanics (QM/MM), classical molecular dynamics simulations (MD) and free‐energy calculations together with NMR spectroscopy were used to elucidate the binding modes in solution. Our work reveals the absence of a potential anion–π interaction between the cationic imidazolium ring and the Lewis basic counteranion, and corroborates a formation of halogen bonding via the Lewis acidic iodine moiety and hydrogen bonding via the backbone hydrogen atoms, with repercussions in the field of organocatalysis

Switching the Spin State of Diphenylcarbene via Halogen Bonding

The interactions between diphenylcarbene DPC and the halogen bond donors CF3I and CF3Br were investigated using matrix isolation spectroscopy (IR, UV-vis, and EPR) in combination with QM and QM/MM calculations. Both halogen bond donors CF3X form very strong complexes with the singlet state of DPC, but only weakly interact with triplet DPC. This results in a switching of the spin state of DPC, the singlet complexes becoming more stable than the triplet complexes. CF3I forms a second complex (type II) with DPC that is thermodynamically slightly more stable. Calculations predict that in this second complex the DPC⋯I distance is shorter than the F3C⋯I distance, whereas in the first (type I) complex the DPC⋯I distance is, as expected, longer. CF3Br only forms the type I complex. Upon irradiation I or Br, respectively, are transferred to the DPC carbene center and radical pairs are formed. Finally, on annealing, the formal C-X insertion product of DPC is observed. Thus, halogen bonding is a powerful new principle to control the spin state of reactive carbenes