Aagaardroberts8501

Bottlebrush copolymers are a versatile class of macromolecular architectures with broad applications in the fields of drug delivery, self-assembly, and polymer networks. Here, the modular nature of graft-through ring-opening metathesis polymerization (ROMP) is exploited to synthesize "ABC" triblock bottlebrush copolymers (TBCs) from polylactic acid (PLA), polyethylene glycol (PEG), and poly(N-isopropylacrylamide) (PNIPAM) macromonomers. Due to the hydrophobicity of their PLA domains, these TBCs self-assemble in aqueous media at room temperature to yield uniform ∼100 nm micelles that can encapsulate a wide range of therapeutic agents. Heating these micellar solutions above the lower critical solution temperature (LCST) of PNIPAM (∼32 °C) induces the rapid formation of multi-compartment hydrogels with PLA and PNIPAM domains acting as physical crosslinks. Following the synthesis and characterization of these materials in vitro, TBC micelles loaded with various biologically active small molecules were investigated as injectable hydrogels for sustained drug release in vivo. Specifically, intratumoral administration of TBCs containing paclitaxel and resiquimod-the latter a potent Toll-like receptor (TLR) 7/8 agonist-into mice bearing subcutaneous CT26 tumors resulted in a significantly enhanced therapeutic index compared to the administration of these two drugs alone. This effect is attributed to the TBC hydrogel maintaining a high local drug concentration, thus reducing systemic immune activation and local inflammation. Collectively, this work represents, to our knowledge, the first example of thermally-responsive TBCs designed for multi-compartment hydrogel formation, establishing these materials as versatile scaffolds for self-assembly and drug delivery.A Cu-catalyzed enantio- and diastereoselective diarylmethylation of 1,3-dicarbonyl compounds is described. Debio 0123 Wee1 inhibitor It is a successful example of constructing all-carbon quaternary stereocenters from 3 °C-H nucleophiles, a challenging topic in synthetic chemistry. In the present work, two contiguous stereocenters are constructed with high levels of stereoselectivity and atom economy. The broad scope of 1,3-dicarbonyl nucleophiles and the tolerance of a wide range of functional groups make this protocol of great importance in the synthesis of chiral diarylmethane compounds.The stereoselective preparation of synthetically versatile vinylboronates from ω-alkenylboronates is achieved through a ruthenium-catalyzed isomerization reaction. A variety of di- and trisubstituted vinylboronates were conveniently produced and could be used as a new starting point for subsequent in situ remote functionalization through either a sequential Ru/Pd or Ru/Cu double catalytic system.The discovery of emergent materials lies at the intersection of chemistry and condensed matter physics. Synthetic chemistry offers a pathway to create materials with the desired physical and electronic structures that support fundamentally new properties. Metal-organic frameworks are a promising platform for bottom-up chemical design of new materials, owing to their inherent chemical predictability and tunability relative to traditional solid-state materials. Herein, we describe the synthesis and magnetic characterization of a new 2,5-dihydroxy-1,4-benzoquinone based material, (NMe2H2)3.5Ga2(C6O4Cl2)3 (1), which features radical-based electronic spins on the sites of a kagomé lattice, a geometric lattice known to engender exotic electronic properties. Vibrational and electronic spectroscopies, in combination with magnetic susceptibility measurements, revealed 1 exhibits mixed valency between the radical-bearing trianionic and diamagnetic tetraanionic oxidation states of the ligand. This unpaired electron density on the ligand forms a partially occupied kagomé lattice where approximately 85% of the lattice sites are occupied with an S = ½ spin. We found that gallium mediates ferromagnetic coupling between ligand spins, creating a ferromagnetic kagomé lattice. By modulation of the interlayer spacing via post-synthetic cation metathesis of 1 to (NMe4)3.5Ga2(C6O4Cl2)3 (2) and (NEt4)2(NMe4)1.5Ga2(C6O4Cl2)3 (3), we determined the nature of the magnetic coupling between neighboring planes is antiferromagnetic. Additionally, we determined the role of the metal in mediating this magnetic coupling by comparison of 2 with the In3+ analogue, (NMe4)3.5In2(C6O4Cl2)3 (4), and we found that Ga3+ supports stronger superexchange coupling between ligand-based spins than In3+. The combination of intraplanar ferromagnetic coupling and interplanar antiferromagnetic coupling exchange interactions suggests these are promising materials to host topological phenomena.We describe an example of a two-electron metal- and ligand-based reduction of Me3SiN3 using uranium(iv) complexes with varying steric properties. Reaction of (C5Me5)2U(CH3)[P(SiMe3)(Ph)] with Me3SiN3 produces the imidophosphorane complex, (C5Me5)2U(CH3)[N[double bond, length as m-dash]P(SiMe3)2(Ph)] through oxidation of phosphorus. However, a similar reaction with a more sterically encumbering phosphido ligand, (C5Me5)2U(CH3)[P(SiMe3)(Mes)] forms the U(iv) complex, (C5Me5)2U[κ 2-(N,N)-N(SiMe3)P(Mes)N(SiMe3)]. In probing the mechanism of this reaction, a U(vi) bis(imido) complex, (C5Me5)2U([double bond, length as m-dash]NSiMe3)[double bond, length as m-dash]N[P(SiMe3)(Mes)] was isolated. DFT calculations show an intramolecular reductive cycloaddition reaction leads to the formation of the U(iv) bis(amido)phosphane from the U(vi) bis(imido) complex. This is a rare example of the isolation of a reaction intermediate in f element chemistry.Gold nanoparticles (AuNPs) are widely used in various applications such as cancer imaging and drug delivery. The functionalisation of AuNPs has been shown to affect their cellular internalisation, accumulation and targeting efficiency. The mechanism of cellular uptake of functionalised AuNPs by different cancer cells is not well understood. Therefore, a detailed understanding of the molecular processes is necessary to improve AuNPs for their selective uptake and fate in specific cellular systems. This knowledge can greatly help in designing nanotags with higher cellular uptake for more selective and specific targeting capabilities with less off-target effects. Here, we demonstrate for the first time a straightforward and non-destructive 3D surface enhanced Raman spectroscopy (SERS) imaging approach to track the cellular uptake and localisation of AuNPs functionalised with an anti-ERα (estrogen receptor alpha) antibody in MCF-7 ERα-positive human breast cancer cells under different conditions including temperature and dynamin inhibition. 3D SERS enabled information rich monitoring of the intracellular internalisation of the SERS nanotags. It was found that ERα-AuNPs were internalised by MCF-7 cells in a temperature-dependent manner suggesting an active endocytosis-dependent mechanism. 3D SERS cell mapping also indicated that the nanotags entered MCF-7 cells using dynamin dependent endocytosis, since dynamin inhibition resulted in the SERS signal being obtained from, or close to, the cell surface rather than inside the cells. Finally, ERα-AuNPs were found to enter MCF-7 cells using an ERα receptor-mediated endocytosis process. This study addresses the role of functionalisation of SERS nanotags in biological environments and highlights the benefits of using 3D SERS for the investigation of cellular uptake processes.We report the excited-state behavior of a structurally simple bis-sulfoxide complex, cis-S,S-[Ru(bpy)2(dmso)2]2+, as investigated by femtosecond pump-probe spectroscopy. The results reveal that a single photon prompts phototriggered isomerization of one or both dmso ligands to yield a mixture of cis-S,O-[Ru(bpy)2(dmso)2]2+ and cis-O,O-[Ru(bpy)2(dmso)2]2+. The quantum yields of isomerization of each product and relative product distribution are dependent upon the excitation wavelength, with longer wavelengths favoring the double isomerization product, cis-O,O-[Ru(bpy)2(dmso)2]2+. Transient absorption measurements on cis-O,O-[Ru(bpy)2(dmso)2]2+ do not reveal an excited-state isomerization pathway to produce either the S,O or S,S isomers. Femtosecond pulse shaping experiments reveal no change in the product distribution. Pump-repump-probe transient absorption spectroscopy of cis-S,S-[Ru(bpy)2(dmso)2]2+ shows that a pump-repump time delay of 3 ps dramatically alters the S,O  O,O product ratio; pump-repump-probe transient absorption spectroscopy of cis-O,O-[Ru(bpy)2(dmso)2]2+ with a time delay of 3 ps uncovers an excited-state isomerization pathway to produce the S,O isomer. In conjunction with low-temperature steady-state emission spectroscopy, these results are interpreted in the context of an excited-state bifurcating pathway, in which the isomerization product distribution is determined not by thermodynamics, but rather as a dynamics driven reaction.Combined computational and experimental studies elucidated the distinctive mechanistic features of electrochemical cobalt-catalyzed C-H oxygenation. A sequential electrochemical-chemical (EC) process was identified for the formation of an amidylcobalt(iii) intermediate. The synthesis, characterization, cyclic voltammetry studies, and stoichiometric reactions of the related amidylcobalt(iii) intermediate suggested that a second on-cycle electro-oxidation occurs on the amidylcobalt(iii) species, which leads to a formal Co(iv) intermediate. This amidylcobalt(iv) intermediate is essentially a cobalt(iii) complex with one additional single electron distributed on the coordinating heteroatoms. The radical nature of the coordinating pivalate allows the formal Co(iv) intermediate to undergo a novel carboxylate-assisted HAT mechanism to cleave the arene C-H bond, and a CMD mechanism could be excluded for a Co(iii/i) catalytic scenario. The mechanistic understanding of electrochemical cobalt-catalyzed C-H bond activation highlights the multi-tasking electro-oxidation and the underexplored reaction channels in electrochemical transition metal catalysis.We herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology. Several of the novel "CLipP"ed lipopeptides exhibited low micromolar MICs and MBCs against both Gram-negative and Gram-positive bacteria. The mechanism of action was then simulated with the MIC data using computational methods.Strategies to capitalize on enolate intermediates generated from stereoselective conjugate borylation to α,β-unsaturated carbonyl systems are surprisingly rare despite the ubiquity of Michael acceptors, and the potential to generate valuable scaffolds bearing multiple stereocenters. Herein, we report a mild and stereoselective copper-catalyzed conjugate borylation/Mannich cyclization reaction. This strategy is feasible with a broad range of Michael acceptors, and can be leveraged to generate versatile borylated tetrahydroquinoline scaffolds bearing three contiguous stereocenters. The synthetic potential of these complex heterocycles has been explored through a series of derivatization studies.