Rhodium(NHC)-Catalyzed <i>O</i>-Arylation of Aryl Bromides

The first example of the rhodium-catalyzed O-arylation of aryl bromides is reported. While the right combination of rhodium species and N-heterocyclic carbene (NHC) offered an effective catalytic system enabling the arylation to proceed, the choice of NHC was determined to be most important. The developed O-arylation protocol has a wide range of substrate scope, high functional group tolerance, and flexibility allowing a complementary route to either N- or O-arylation depending on the choice of NHC

High-Affinity Recognition of Lanthanide(III) Chelate Complexes by a Reprogrammed Human Lipocalin 2

Human lipocalin 2 (Lcn2), also known as neutrophil gelatinase-associated lipocalin (NGAL), which naturally scavenges bacterial ferric siderophores, has been engineered to specifically bind rare-earth and related metal ions as chelate complexes with [(R)-2-amino-3-(4-aminophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-NH2-Bn−CHX-A′′-DTPA). To this end, 12 amino acid residues in the ligand pocket of Lcn2, which is formed by four loops at the open end of an eight-stranded β-barrel, were subjected to targeted random mutagenesis, and from the resulting library, variants with binding activity for the Me·DTPA group were selected using the method of bacterial phage display. One promising candidate was further developed in several cycles of in vitro affinity maturation using partial random mutagenesis and selection (via phage display and/or Escherichia coli colony screening) under conditions of increasing stringency. As result, an Lcn2 variant was obtained that binds Y·DTPA with a dissociation constant as low as 400 pM. The Lcn2 variant specifically recognizes the artificial ligand, as exemplified in (competitive) ELISA and real-time surface plasmon resonance analyses. DTPA-complexed Y3+, Tb3+, Gd3+, and Lu3+ are most tightly bound, comprising metal ions whose isotopes are in common use for radiotherapy and imaging. All of the Lcn2 variants are stably folded and can be functionally produced in high yield in E. coli. X-ray crystallographic analyses show that the new ligand is well-accommodated in the central cavity of the engineered lipocalin, whose fold is largely preserved, but that the mode of binding differs from the one seen with the natural ligand Fe·enterobactin. This structural study reveals analogies but also differences with respect to previously described antibody−metal chelate complexes. Notably, the functionalized side chain of DTPA protrudes from the ligand pocket of the lipocalin in such a way that its conjugates (with other haptens, for example) are recognized too. With their small sizes and robust fold based on a single polypeptide chain, the engineered Lcn2 variants provide novel modules and/or fusion partners for radionuclide−chelate capturing strategies that bear promise for medical diagnostics and therapy

Rhodium(NHC)-Catalyzed <i>O</i>-Arylation of Aryl Bromides

The first example of the rhodium-catalyzed O-arylation of aryl bromides is reported. While the right combination of rhodium species and N-heterocyclic carbene (NHC) offered an effective catalytic system enabling the arylation to proceed, the choice of NHC was determined to be most important. The developed O-arylation protocol has a wide range of substrate scope, high functional group tolerance, and flexibility allowing a complementary route to either N- or O-arylation depending on the choice of NHC

Biomaterial-Mediated Exogenous Facile Coating of Natural Killer Cells for Enhancing Anticancer Efficacy toward Hepatocellular Carcinoma

Natural killer (NK) cells exhibit a good therapeutic efficacy against various malignant cancer cells. However, the therapeutic efficacy of plain NK cells is relatively low due to inadequate selectivity for cancer cells. Therefore, to enhance the targeting selectivity and anticancer efficacy of NK cells, we have rationally designed a biomaterial-mediated ex vivo surface engineering technique for the membrane decoration of cancer recognition ligands onto NK cells. Our designed lipid conjugate biomaterial contains three major functional moieties: (1) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) lipid for cell membrane anchoring, (2) polyethylene glycol for intracellular penetration blocker, and (3) lactobionic acid (LBA) for cancer recognition. The biomaterial was successfully applied to NK cell surfaces (LBA-NK) to enhance recognition and anticancer functionalities, especially toward asialoglycoprotein receptor (ASGPR)-overexpressing hepatocellular carcinoma. Highly efficient and homogeneous NK cell surface editing was achieved with a simple coating process while maintaining intrinsic properties of NK cells. LBA-NK cells showed potential ASGPR-mediated tumor cell binding (through LBA-ASGPR interaction) and thereby significantly augmented anticancer efficacies against HepG2 liver cancer cells. Thus, LBA-NK cells can be a novel engineering strategy for the treatment of liver cancers via facilitated immune synapse interactions in comparison with currently available cell therapies

Intermolecular Oxidative C–N Bond Formation under Metal-Free Conditions: Control of Chemoselectivity between Aryl sp² and Benzylic sp³ C–H Bond Imidation

A new synthetic approach toward intermolecular oxidative C–N bond formation of arenes has been developed under transition-metal-free conditions. Complete control of chemoselectivity between aryl sp2 and benzylic sp3 C–H bond imidation was achieved by the choice of nitrogen sources, representatively being phthalimide and dibenzenesulfonimide, respectively

Highly Efficient and Versatile Synthesis of Polyarylfluorenes via Pd-Catalyzed C−H Bond Activation

A facile protocol for the Pd-catalyzed preparative synthesis of fluorene derivatives has been developed. While a wide range of fluorenes were easily obtained with high efficiency and selectivity under mild conditions, excellent functional group tolerance was also demonstrated. On the basis of Hammett and KIE studies, the present reaction is proposed to proceed via a base-assisted deprotonative metalation pathway

Intramolecular Oxidative Diamination and Aminohydroxylation of Olefins under Metal-Free Conditions

A metal-free procedure that is simple to operate and convenient to handle was developed for the facile intramolecular oxidative diamination of olefins using an iodobenzene diacetate oxidant and a halide additive to furnish bisindolines at room temperature. The present reaction is featured by mild conditions, a broad substrate scope, and excellent functional group tolerance. The same protocol was successfully extended to the aminohydroxylation

Comparison of the first three normal modes and principal components.

<p>Overlapping ribbon conformations for the three lowest normal modes are shown at t = 0 (red) and (blue) with the normalized eigenvector vibrational amplitudes scaled by a factor of 200. The normal mode index corresponds to specific vibrational frequencies as follows:  = 1 (hinge-bend), 0.80 cm;  = 2 (twist), 1.72 cm;  = 3 (tilt), 3.08 cm. Overlapping ribbon conformations for the three largest amplitude principal components (p = 1, 2, 3) are shown with the reference structure (red) as displacements scaled by a factor of 200 standard deviations along each principal component (blue) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009180#pone.0009180-Molecular1" target="_blank">[74]</a>.</p

MD and X-ray results for distances between binding sites of PDC109 and PhC.

<p>Distances are in Å and were determined by averaging through MD trajectories (protomer A) and from the crystal structure (protomers A and B, *PDB ID: 1h8p). Distances for tryptophans were calculated between the six-carbon ring centers of sidechain indoles and the PhC quaternary ammonium nitrogen. Distances for tyrosines were calculated between sidechain hydroxyl oxygens and the average position of three PhC phosphate oxygens. Average MD distances and standard deviations were calculated using the initial 230 ns trajectories because PhC started to detach from the binding pocket of PDC109/a at about 240 ns.</p

Distances between the ligand and protein interaction sites in PDC109 domains.

<p>Time series are shown for distances between the quaternary ammonium nitrogen of PhC and the center of geometry of six carbon atoms in indole rings of W47 (A), W93 (B), W58 (C), W106 (D); and between the average position of anionic PhC phosphoryl oxygens and the hydroxyl oxygens of Y30 (E), Y75 (F), Y54 (G), Y100 (H), Y60 (I), Y108 (J).</p