Covalent and non-covalent albumin binding of Au(i) bis-NHCs via post-synthetic amide modification

Recent decades have witnessed the emergence of Au(i) bis-N-heterocyclic carbenes (NHCs) as potential anticancer agents. However, these systems exhibit little interaction with serum proteins (e.g., human serum albumin), which presumably impacts their pharmacokinetic profile and tumor exposure. Anticancer drugs bound to human serum albumin (HSA) often benefit from significant advantages, including longer circulatory half-lives, tumor targeted delivery, and easier administration relative to the drug alone. In this work, we present Au(i) bis-NHCs complexes, 7 and 9, capable of binding to HSA. Complex 7 contains a reactive maleimide moiety for covalent protein conjugation, whereas its congener 9 contains a naphthalimide fluorophore for non-covalent binding. A similar drug motif was used in both cases. Complexes 7 and 9 were prepared from a carboxylic acid functionalized Au(i) bis-NHC (complex 2) using a newly developed post-synthetic amide functionalization protocol that allows coupling to both aliphatic and aromatic amines. Analytical, and in vitro techniques were used to confirm protein binding, as well as cellular uptake and antiproliferative activity in A549 human lung cancer cells. The present findings highlight a hitherto unexplored approach to modifying Au(i) bis-NHC drug candidates for protein ligation and serve to showcase the relative benefits of covalent and non-covalent HSA binding.

Au(i) bis-N-heterocyclic carbenes (NHCs) functionalized using an amide linker were found to bind to human serum albumin (HSA) in covalent and non-covalent fashion. The solubility and in vitro anti-cancer activity of these new conjugates were studied.     

Probing the water coordination of protein-targeted MRI contrast agents by pulsed ENDOR spectroscopy.

A novel methodology based on electron-nuclear double resonance (ENDOR) spectroscopy is used for the direct determination of the water coordination number (q) of gadolinium-based magnetic resonance imaging (MRI) contrast agents. Proton ENDOR spectra can be obtained at approximately physiological concentrations for metal complexes in frozen aqueous solutions either in the presence or absence of protein targets. It is shown that, depending on the structure of the co-ligand, the water hydration number of a complex in aqueous solution can be significantly different to when the complex is noncovalently bound to a protein. From the ENDOR spectra of the exchangeable protons, precise information on the metal-proton distance can be derived as well. These essential parameters directly correlate with the efficacy of MRI contrast agents and should therefore aid the development of novel, highly efficient compounds targeted to various proteins.     

Rapid on-chip postcolumn labeling and high-resolution separations of DNA

When performing genetic analysis on microfluidic systems, labeling the sample DNA for detection is a critical preparation step. Labeling procedures often involve fluorescently tagged primers and PCRs, which lengthen experimental run times and introduce higher levels of complexity, increasing the overall cost per analysis. Alternatively, on-chip labeling techniques based on intercalating dyes permit rapid labeling of DNA fragments. However, as noted in the literature, the stochastic nature of dye-DNA complex formation hinders the native electrophoretic migration of DNA fragments, degrading the separation resolution. In this study, we present a novel method of controllably labeling DNA fragments at the end of the electrophoretic separation channel in a glass microfluidic chip. Permitting the DNA to separate and labeling just before detection, achieves the rapid labeling associated with intercalators while maintaining the high resolution of native DNA separations. Our analyses are completed in minutes, rather than the hours typical of sample prelabeling. We demonstrate an electrophoretic microchip-based intercalator labeling technique that achieves higher resolution performance than reported in the literature to date.     

Exact exponent for the number of persistent spins in the zero-temperature dynamics of the one-dimensional Potts model

For the zero-temperature Glauber dynamics of theq-state Potts model, the fractionr(q, t) of spins which never flip up to timet decays like a power lawr(q, t)t ^–(q) when the initial condition is random. By mapping the problem onto an exactly soluble one-species coagulation model (A+AA) or alternatively by transforming the problem into a free-fermion model, we obtain the exact expression of (q) for all values ofq. The exponent (q) is in general irrational, (3)=0.53795082..., (4)=0.63151575..., ..., with the exception ofq=2 andq=, for which (2)=3/8 and ()=1.     

Protection of the Hydroxyphosphinyl Function of Phosphinic Dipeptides by Adamantyl. Application to the Solid-Phase Synthesis of Phosphinic Peptides

To develop solid-phase synthesis of phosphinic peptides, different FmocXaaPsi{PO(OAd)CH(2)}XaaOH building blocks have been prepared, where Fmoc is (fluorenylmethoxy)carbonyl. In this respect, the protection of the hydroxyphosphinyl function in these phosphinic dipeptides by the adamantyl group turns out to be convenient. The phosphinic adamantyl esters are completely stable in basic conditions and can be removed under relatively mild acidic conditions. Using these building blocks, despite the bulkiness of the adamantyl group, no particular problem of coupling was observed during the solid-phase synthesis of phosphinic peptides by the Fmoc strategy. The developed methodology is of particular interest to facilitate the development of potent inhibitors of zinc-metalloproteases.     

Non-empirical calculations on the rydberg states of ethylene

Different methods for representing the upper orbitals in Rydberg transitions are tested by means of a series of ab initio SCF and CI calculations for ethylene and various properties for such diffuse united-atom species are reported. Calculated transition energies indicates the maximum separation between individual components of the (π,3d) Rydberg species to be in the 0.1-0.2 range, with similarly small energy separations being obtained for the corresponding (π, 3p) states     

Hexakis(isopropylthio)-1,5-hexadien-3-yne and its fluorescent Ag(I) coordination polymers: assembly of helicates with thioether sites

A new thioether-rich ligand with a conjugated dienyne backbone and its fluorescent Ag(I) coordination networks have been synthesized and characterized by single crystal X-ray diffraction studies, which reveal that the supramolecular architectures of the networks contain assembled helicates with thioether sites.     

The thermodynamic properties of acetals+heptane mixtures at 298.15 K

Excess enthalpies and excess volumes were determined at 298.15 K for: dimethoxymethane+heptane, diethoxymethane+heptane, 1,1-dimethoxyethane+heptane, 1,1-diethoxyethane+heptane, 2,2-dimethoxypropane+heptane and 1,1-diethoxypropane+heptane.     

Einen Trennungsgang zur quantitativen Bestimmung von Keto- und Aminos?uren in kleinen Mengen des Liquor Cerebrospinalis

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