One-pot homologation of boronic acids : a platform for diversity-oriented synthesis

Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor

Disclination Unbinding Transition in Quantum Hall Liquid Crystals

We derive the the long-wavelength elastic theory for the quantum Hall smectic state starting from the Hartree-Fock approximation. Dislocations in this state lead to an effective nematic model for $T>0$, which undergoes a disclination unbinding transition from a phase with algebraic orientational order into an isotropic phase. We obtain transition temperatures which are in qualitative agreement with recent experiments which have observed large anisotropies of the longitudinal resistivities in half-filled Landau levels, lending credence to the liquid crystal interpretation of experiments.Comment: Added explanation for spin dependence of anisotropic strength: The reason for this spin oscillation is simple: in the energetics of Eqs. (4-6), there is an energy scale $e^2/l_b$ that decreases with increasing filling factor $\nu$; simultaneously the matrix elements of the Coulomb interaction [Eq. (3)] increase with increasing LL index $L$, resulting in the observed spin dependenc

Identification of a novel class of autotaxin inhibitors through cross-screening

Three novel series were generated in order to mimic the pharmacophoric features displayed by lead compound AM095, a Lysophosphatidic acid (LPA1) receptor antagonist. Biological evaluation of this array of putative LPA1 antagonists led us to the discovery of three novel series of inhibitors of the ecto-enzyme Autotaxin (ATX), responsible for LPA production in blood, with potencies in the range 1 – 4 μM accompanied with good (> 100 μg/mL) solubility

One-pot homologation of boronic acids : a platform for diversity-oriented synthesis

Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor

Finite Temperature Magnetism in Fractional Quantum Hall Systems: Composite Fermion Hartree-Fock and Beyond

Using the Hamiltonian formulation of Composite Fermions developed recently, the temperature dependence of the spin polarization is computed for the translationally invariant fractional quantum Hall states at $\nu=1/3$ and $\nu=2/5$ in two steps. In the first step, the effect of particle-hole excitations on the spin polarization is computed in a Composite Fermion Hartree-Fock approximation. The computed magnetization for $\nu=1/3$ lies above the experimental results for intermediate temperatures indicating the importance of long wavelength spin fluctuations which are not correctly treated in Hartree-Fock. In the second step, spin fluctuations beyond Hartree-Fock are included for $\nu=1/3$ by mapping the problem on to the coarse-grained continuum quantum ferromagnet. The parameters of the effective continuum quantum ferromagnet description are extracted from the preceding Hartree-Fock analysis. After the inclusion of spin fluctuations in a large-N approach, the results for the finite-temperature spin polarization are in quite good agreement with the experiments.Comment: 10 pages, 8 eps figures. Two references adde

Molecular Simulation of ?v?6 Integrin Inhibitors

The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin ?v?6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of ?v?6 in complex with its natural ligand, pro-TGF-?1, show the persistence over time of a bidentate Arg-Asp ligand-receptor interaction and a metal chelate interaction between an aspartate on the ligand and an Mg2+ ion in the active site. This is typical of RGD binding ligands. Additional binding site interactions, which are not observed in the static crystal structure, are also identified. We investigate an RGD mimetic, which serves as a framework for a series of potential ?v?6 antagonists. The scaffold includes a derivative of the widely utilized 1,8-naphthyridine moiety, for which we present force field parameters, to enable MD and relative free energy perturbation (FEP) simulations. The MD simulations highlight the importance of hydrogen bonding and cation-? interactions. The FEP calculations predict relative binding affinities, within 1.5 kcal mol-1, on average, of experiments

Spontaneous Interlayer Coherence in Double-Layer Quantum Hall Systems: Symmetry Breaking Interactions, In-Plane Fields and Phase Solitons

At strong magnetic fields double-layer two-dimensional-electron-gas systems can form an unusual broken symmetry state with spontaneous inter-layer phase coherence. The system can be mapped to an equivalent system of pseudospin $1/2$ particles with pseudospin-dependent interactions and easy-plane magnetic order. In this paper we discuss how the presence of a weak interlayer tunneling term alters the properties of double-layer systems when the broken symmetry is present. We use the energy functional and equations of motion derived earlier to evaluate the zero-temperature response functions of the double-layer system and use our results to discuss analogies between this system and Josephson-coupled superconducting films. We also present a qualitative picture of the low-energy charged excitations of this system. We show that parallel fields induce a highly collective phase transition to an incommensurate state with broken translational symmetry.Comment: 26 pages, RevTex, 8 postscript figures (submitted to Phys. Rev. B

Recurrence for discrete time unitary evolutions

We consider quantum dynamical systems specified by a unitary operator U and an initial state vector \phi. In each step the unitary is followed by a projective measurement checking whether the system has returned to the initial state. We call the system recurrent if this eventually happens with probability one. We show that recurrence is equivalent to the absence of an absolutely continuous part from the spectral measure of U with respect to \phi. We also show that in the recurrent case the expected first return time is an integer or infinite, for which we give a topological interpretation. A key role in our theory is played by the first arrival amplitudes, which turn out to be the (complex conjugated) Taylor coefficients of the Schur function of the spectral measure. On the one hand, this provides a direct dynamical interpretation of these coefficients; on the other hand it links our definition of first return times to a large body of mathematical literature.Comment: 27 pages, 5 figures, typos correcte

Emergence of small molecule non-RGD-mimetic inhibitors for RGD integrins

The RGD integrins are recognized therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence (arginineglycine-aspartic acid) of the natural ligands; however, the RGD-mimetic antagonists for αIIbβ3 have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrin-therapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic. This 2 perspective will discuss the discovery of these non-RGD-mimetic inhibitors, and the progress that has been made in this promising new chemotype

Recognition of cancer warning signs and anticipated time to help-seeking in a population sample of adults in the UK

Background: Not recognising a symptom as suspicious is a common reason given by cancer patients for delayed help-seeking; but inevitably this is retrospective. We therefore investigated associations between recognition of warning signs for breast, colorectal and lung cancer and anticipated time to help-seeking for symptoms of each cancer. Methods: Computer-assisted telephone interviews were conducted with a population-representative sample (N=6965) of UK adults age greater than or equal to50 years, using the Awareness and Beliefs about Cancer scale. Anticipated time to help-seeking for persistent cough, rectal bleeding and breast changes was categorised as >2 vs less than or equal to2 weeks. Recognition of persistent cough, unexplained bleeding and unexplained lump as cancer warning signs was assessed (yes/no). Associations between recognition and help-seeking were examined for each symptom controlling for demographics and perceived ease of health-care access. Results: For each symptom, the odds of waiting for >2 weeks were significantly increased in those who did not recognise the related warning sign: breast changes: OR=2.45, 95% CI 1.47–4.08; rectal bleeding: OR=1.77, 1.36–2.30; persistent cough: OR=1.30, 1.17–1.46, independent of demographics and health-care access. Conclusion: Recognition of warning signs was associated with anticipating faster help-seeking for potential symptoms of cancer. Strategies to improve recognition are likely to facilitate earlier diagnosis