Structure-Activity Relationship Analysis of YM155 for Inducing Selective Cell Death of Human Pluripotent Stem Cells

Despite great potential for regenerative medicine, the high tumorigenic potential of human pluripotent stem cells (hPSCs) to form undesirable teratoma is an important technical hurdle preventing safe cell therapy. Various small molecules that induce the complete elimination of undifferentiated hPSCs, referred to as “stemotoxics,” have been developed to facilitate tumor-free cell therapy, including the Survivin inhibitor YM155. In the present work, based on the chemical structure of YM155, total 26 analogs were synthesized and tested for stemotoxic activity toward human embryonic stem cells (hESCs) and induced PSCs (iPSCs). We found that a hydrogen bond acceptor in the pyrazine ring of YM155 derivatives is critical for stemotoxic activity, which is completely lost in hESCs lacking SLC35F2, which encodes a solute carrier protein. These results suggest that hydrogen bonding interactions between the nitrogens of the pyrazine ring and the SLC35F2 protein are critical for entry of YM155 into hPSCs, and hence stemotoxic activity

Magnetic Control of Optical Reflectance from Metallic Thin Film Using Surface Plasmon Resonance and Faraday Rotation

We demonstrate magnetic control of optical reflectance with no ferromagnetic material via combining the Faraday rotation and the surface plasmon resonance (SPR) in a Kretschman configuration under magnetic fields < 0.5 T. The SPR produces the polarization sensitive reflectance from the Au or Ag thin film coated on a N-BK7 prism in which the Faraday rotation occurs. The gold (Au) or silver (Ag) metal film as a plasmonic film somewhat acts as an incident angle-dependent reflection polarizer that can sensitively sense the polarization change induced by the Faraday rotation that occurs in a prism. We find that combination of Faraday rotation and the surface plasmon can induce a significant magnetic modulation of reflectance normalized with respect to that obtained with no magnetic fields at a specific incident angle of light. The magnetic control of optical reflectance presented may find an application in polarizer-free photonic devices with no ferromagnetic material for magneto-optical modulation

A Plasmonic Fiber Based Glucometer and Its Temperature Dependence

We present the plasmonic fiber based optical glucometer. A thin gold layer is coated on clad-free core of multimode optical fiber along 3 cm length to excite surface plasmons at 632.8 nm wavelength. Glucose oxidase is immobilized on the metal surface for glucose sensing. The effective surface refractive index increases by gluconic acid and hydrogen peroxide that are generated upon glucose injection, leading to plasmonic condition change with a consequence of optical power change at the fiber output. We obtain limit of detection of glucose concentration of 6.75 mg/dL, indicating higher sensitivity than the wavelength interrogating SPR glucometer that uses a spectrometer of 1nm spectral resolution. The coefficient of variation is 8.6% at a glucose concentration of 80 mg/dL at room temperature. We also examine the effects of ambient temperature variations from −10 °C to 40 °C on the performance of the presented sensor and compared them with those on commercially available glucometers that are based on enzyme electrodes. We find that the presented fiber sensor produced standard deviation of 12.1 mg/dL at a glucose concentration of 80 mg/dL under such varying temperature, which is, even without additional temperature correction function, comparable to the commercialized ones

Mechanistic Study of Metal-Ligand Cooperativity in Mn(II)-Catalyzed Hydroborations: Hemilabile SNS Ligand Enables Metal Hydride-Free Reaction Pathway

© A combined experimental and mechanistic study of the chemoselective hydroboration of carbonyls by the paramagnetic bis-amido Mn[SMeNSMe]2 complex (1) is described. The catalyst allows for room-temperature hydroboration of carbonyls at low catalyst loadings (0.1 mol %) and reaction times (<30 min). A series of mechanistic studies highlight the significance of bifunctional amido bis(thioether) ligand L to the success of the reaction, insight otherwise difficult to attain in paramagnetic systems. Kinetic studies using variable time normalization analysis revealed no unusual reaction kinetics, indicating the absence of side reactions. A borylated analogue of L was observed and characterized via mass spectrometry. Density functional theory (DFT) calculations showed that thioether hemilability of L is crucial during catalysis for providing the active coordinating site. Also, the frequently proposed Mn-H intermediate was found not to be the active species responsible for catalysis. Instead, an inner-sphere reaction pathway with carbonyl coordination to the metal center and amido-promoted B-H reactivity is proposed to be operative.11Nsciescopu

Spin-state crossover in photo-catalyzed nitrile dihydroboration via Mn-thiolate cooperation

The role of S-donors in ligand-assisted catalysis using first-row metals has not been broadly investigated. Herein is described a combined experimental and computational mechanistic study of the dihydroboration of nitriles with pinacolborane (HBpin) catalyzed by the Mn(I) complex, Mn(kappa(3)-(SNS)-N-Me)(CO)(3), that features thioether, imine, and thiolate donors. Mechanistic studies revealed that catalysis requires the presence of UV light to enter and remain in the catalytic cycle and evidence is presented for loss of two CO ligands. Stoichiometric reactions showed that HBpin reduces the imine N=C of the ligand backbone in the absence of nitrile, forming an inactive off-cycle by-product. DFT calculations showed that the bifunctional thiolate donor, coordinative flexibility of the (SNS)-N-Me ligand, and access to an open-shell intermediate are all crucuial to accessing low-energy intermediates during catalysis.11Nsciescopu

Asymmetric Synthesis of (−)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions

The versatile synthesis of (&minus;)-6-desmethyl-fluvirucinine A1 was accomplished at a 24% overall yield through a thirteen-step process from a known vinylpiperidine. The key part involved the elaboration of the distal stereocenters and a macrolactam skeleton via conformationally-induced diastereocontrol and the iterative aza-Claisen rearrangements of lactam precursors