E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist of a target binding unit, a linker, and an E3 ligase binding moiety. The chemically-induced formation of ternary complexes leads to ubiquitination and proteasomal degradation of target proteins. Among the plethora of E3 ligases, only a few have been utilized for the novel PROTAC technology. However, extensive knowledge on the preparation of E3 ligands and their utilization for PROTACs has already been acquired. This review provides an in-depth analysis of synthetic entries to functionalized ligands for the most relevant E3 ligase ligands, i.e. CRBN, VHL, IAP, and MDM2. Less commonly used E3 ligase and their ligands are also presented. We compare different preparative routes to E3 ligands with respect to feasibility and productivity. A particular focus was set on the chemistry of the linker attachment by discussing the synthetic opportunities to connect the E3 ligand at an appropriate exit vector with a linker to assemble the final PROTAC. This comprehensive review includes many facets involved in the synthesis of such complex molecules and is expected to serve as a compendium to support future synthetic attempts towards PROTACs.

The First Isolable Low-valent Ferrocene Enabling the Application of Unprecedented Ferrocene Anolyte

Here, we report the first isolable low-valent biscyclopentadienyl iron complexes stabilized by NHC-functionalized ligands (NHC-Cps), which were characterized by electron paramagnetic resonance (EPR) and ⁵⁷Fe Mössbauer spectroscopy. Additional theoretical studies on these formally low-valent ferrocene complexes clearly explain the origin of their thermodynamic stability and the orbital interactions between iron and NHC-Cp. Exploiting the facile Fe(II/I) redox chemistry, we successfully demonstrated that the NHC-Fc compounds can be applied as the first example of ferrocene anolyte for redox-flow batteries. These low-valent species will not only deepen our understanding of the intrinsic chemistry of low-valent ferrocene but have the potential to open the way for the rational design of low-valent metallocene derivatives for various applications.

Nanoscalpel based on magnetic discs and aptamers effectively and targeted destroy tumor cell

The aim of the research. To investigate the antitumor effi cacy of three-layer magnetic nanodiscs (Au / Ni / Au) with a quasi-dipole structure, functionalized with biorecognizing molecules of a tumor. Material and methods. Th ree-layer magnetic nanodiscs (Au / Ni / Au) 500 nm in size (were obtained by micro- and nanoelectronic technologies. Aptamers to ascites cells of Ehrlich carcinoma were used to functionalize magnetic nanodiscs. Th iol groups were used to bind disks to aptamers. As a model of tumor cells Ehrlich’s ascites carcinoma cells were used, and the cells were magnetically infl uenced by an alternating magnetic fi eld (50 Hz, 100 Oe). Results. Magnetic nanodiscs have magnetic anisotropy, which proves their high sensitivity to magnetic stimuli. Magnetic nanodiscs start the processes of cell death in the culture of ascites cells for two hours. Presumably, magnetic nanodiscs use aptamers to bind to the cell membrane protein fi lamin A, a structural component of the cytoskeleton that plays an important role in cell signaling and, when exposed to a variable magnetic, cause destruction of the cell membrane and cell death. Conclusion. Microsurgery of malignant tumors using a nanoscalpel based on functionalized ligands that recognize tumor sites can be used to remove single tumor cells during surgery

Direct observation of nanoparticle-surfactant assembly and jamming at the water-oil interface

Electrostatic interactions between nanoparticles (NPs) and functionalized ligands lead to the formation of NP surfactants (NPSs) that assemble at the water-oil interface and form jammed structures. To understand the interfacial behavior of NPSs, it is necessary to understand the mechanism by which the NPSs attach to the interface and how this attachment depends on the areal coverage of the interface. Through direct observation with high spatial and temporal resolution, using laser scanning confocal microscopy and in situ atomic force microscopy (AFM), we observe that early-stage attachment of NPs to the interface is diffusion limited and with increasing areal density of the NPSs, further attachment requires cooperative displacement of the previously assembled NPSs both laterally and vertically. The unprecedented detail provided by in situ AFM reveals the complex mechanism of attachment and the deeply nonequilibrium nature of the assembly.

Low-Valent Ferrocenes

Here, we report the first isolable low-valent biscyclopentadienyl iron complexes stabilized by NHC-functionalized ligands (NHC-Cps), which were characterized by electron paramagnetic resonance (EPR) and ⁵⁷Fe Mössbauer spectroscopy. Additional theoretical studies on these formally low-valent ferrocene complexes clearly explain the origin of their thermodynamic stability and the orbital interactions between iron and NHC-Cp. Exploiting the facile Fe(II/I) redox chemistry, we successfully demonstrated that the NHC-Fc compounds can be applied as anolytes for redox-flow batteries. These low-valent species will not only deepen our understanding of the intrinsic chemistry of low-valent ferrocene but have the potential to open the way for rational design of highly-reduced metallocene derivatives for various applications.

Low-Valent Ferrocenes

Here, we report the first isolable low-valent biscyclopentadienyl iron complexes stabilized by NHC-functionalized ligands (NHC-Cps), which were characterized by electron paramagnetic resonance (EPR) and ⁵⁷Fe Mössbauer spectroscopy. Additional theoretical studies on these formally low-valent ferrocene complexes clearly explain the origin of their thermodynamic stability and the orbital interactions between iron and NHC-Cp. Exploiting the facile Fe(II/I) redox chemistry, we successfully demonstrated that the NHC-Fc compounds can be applied as anolytes for redox-flow batteries. These low-valent species will not only deepen our understanding of the intrinsic chemistry of low-valent ferrocene but have the potential to open the way for rational design of highly-reduced metallocene derivatives for various applications.