Automated chemical synthesis: From resins to instruments

Summary Solid-phase organic synthesis is now a prevalent activity in drug discovery. In keeping with this keen interest is the need to develop reliable automated synthesis instrumentation as well as polymeric supports and linkers suitable for the full range of organic synthesis applications. In this paper, we review our activities in the development of new and enabling tools for automated chemical synthesis, including the following: (i) new solid supports such asArgoGel (PS-PEG-based) andArgo-X203 (PS-based); and (ii) theNautilus 2400 system, a fully closed and inert automated chemistry development workstation. Selected chemistry optimization and synthesis examples performed on the Nautilus and new solid supports will be described.     

Asymptotic Behavior of a Stationary Silo with Absorbing Walls

We study the nearest neighbors one dimensional uniform q-model of force fluctuations in bead packs,⁽¹⁾ a stochastic model to simulate the stress of granular media in two dimensional silos. The vertical coordinate plays the role of time, and the horizontal coordinate the role of space. The process is a discrete time Markov process with state space ^{1,...,N}. At each layer (time), the weight supported by each grain is a random variable of mean one (its own weight) plus the sum of random fractions of the weights supported by the nearest neighboring grains at the previous layer. The fraction of the weight given to the right neighbor of the successive layer is a uniform random variable in [0, 1] independent of everything. The remaining weight is given to the left neighbor. In the boundaries, a uniform fraction of the weight leans on the wall of the silo. This corresponds to absorbing boundary conditions. For this model we show that there exists a unique invariant measure. The mean weight at site i under the invariant measure is i(N+1–i); we prove that its variance is (i(N+1–i))²+O(N ³) and the covariances between grains ij are of order O(N ³). Moreover, as N, the law under the invariant measure of the weights divided by N ² around site (integer part of) rN, r(0, 1), converges to a product of gamma distributions with parameters 2 and 2(r(1–r))^–1 (sum of two exponentials of mean r(1–r)/2). Liu et al. ⁽²⁾ proved that for a silo with infinitely many weightless grains, any product of gamma distributions with parameters 2 and 2/ with [0, ) are invariant. Our result shows that as the silo grows, the model selects exactly one of these Gamma's at each macroscopic place.     

Exact Mean-Field Solutions of the Asymmetric Random Average Process

We consider the asymmetric random average process (ARAP) with continuous mass variables and parallel discrete time dynamics studied recently by Krug/Garcia and Rajesh/Majumdar [both J. Statist. Phys. 99 (2000)]. The model is defined by an arbitrary state-independent fraction density function (r) with support on the unit interval. We examine the exactness of mean-field steady-state mass distributions in dependence of and identify as a conjecture based on high order calculations the class of density functions yielding product measure solutions. Additionally the exact form of the associated mass distributions P(m) is derived. Using these results we show examplary the exactness of the mean-field ansatz for monomial fraction densities (r)=(n–1) r ^n–2 with n2. For verification we calculate the mass distributions P(m) explicitly and prove directly that product measure holds. Furthermore we show that even in cases where the steady state is not given by a product measure very accurate approximants can be found in the class .     

Local observables and particle statistics I

We consider the family of those states which become asymptotically indistinguishable from the vacuum for observations in far away regions of space. The pure states of this family may be subdivided into superselection sectors labelled by generalized charge quantum numbers. The principle of locality implies that within this family one may define a natural product composition (leading for instance from single particle states ton-particle states). Intrinsically associated with then-fold product of states of one sector there is a unitary representation ofP ⁽ⁿ⁾, the permutation group ofn elements, analogous in its role to that arising in wave mechanics from the permutations of the arguments of ann-particle wave function. We show that each sector possesses a statistics parameter which determines the nature of the representation ofP ⁽ⁿ⁾ for alln and whose possible values are 0, ±d ^–1 (d a positive integer). A sector with 0 has a unique charge conjugate (antiparticle states); if =d ^–1 the states of the sector obey para-Bose statistics of orderd, if =–d ^–1 they obey para-Fermi statistics of orderd. Some conditions which restrict to ± 1 (ordinary Bose or Fermi statistics) are given.     

μ+SR and Mössbauer studies of low dimensional magnetic ordering in ilvaite

Ilvaite reveals a quasi one dimensional ferromagnetic order along Fe chains between 50–120K. Both Mössbauer spectroscopy and ⁺SR reveal the onset of long range order below 120K with spin dynamics in the MHz range which is interpreted with relatively slowly moving wide domain boundaries. Below 50K the individual chains couple antiferromagnetically, yet a considerable fraction of dynamical spins is detected from ⁺SR down to low temperature.Work supported by the German Federal Minister of Research and Technology (BMFT) under contract Nr. 03-LI3-BRA.     

A combinatorial method for constructing libraries of long peptides displayed by filamentous phage

Summary We describe the construction and screening of a random peptide library displayed by filamentous phage. The peptides are expressed in multiple copies on the filamentous phage M13 as amino-terminal fusions with the major coat protein, the product of gene VIII. These libraries are efficiently screened for reactive peptides, using a combination of panning in solution followed by a plaque lift assay. Advantages of this system are that both high- and low-affinity phage clones are simultaneously identified and the analysis of non-reactive phage is minimized. The vector system utilized to construct this library enables it to be used for the construction of peptide libraries employing a combinatorial cloning strategy. This feature makes it especially suitable for construction of peptide libraries using codon-based oligonucleotide synthesis. The vectors also allow rapid optimization and modification of lead peptides by codon-based mutagenesis. A 20-amino acid long random peptide library of 1 × 10⁹ members was constructed and screened for peptides that bound to (i) a monoclonal antibody recognizing the amino-terminus of -endorphin; (ii) a monoclonal antibody recognizing a peptide epitope derived from the v -ros oncogene product; and (iii) the constant region of murine IgG2b. The approach described here provides a means for the construction of customized libraries that can be screened with a variety of target molecules.     

The three-dimensional transfer-integral method and its test by a harmonic crystal

The ground state of a simple-cubic crystal is assumed to be a product of single-particle functions and nearest-neighbor (NN) correlation functions. In this so called NNCA (NN-Correlation Approximation) the transfer-integral (TI) method allows an exact integration of ² over the coordinates in all cubic planes but one, leading to the probability-densityP for this plane. If only NN-correlations are retained inP (2^nd NNCA) the TI-method leads to the probability-density for a row. Finally, after a 3^rd NNCA, the 1- and 2-particle probability densities are obtained, which are used to calculate the expectation valueE = |H| of a Hamiltonian with arbitrary 2-body interaction.—For harmonic NN-interactions the 2^nd and 3^rd NNCA become exact, andE differs only by 1% from the exact result. The inclusion of small next-NN-interactions still improves this result, though the 2^nd and 3^rd NNCA are no longer exact.     

Inertia,relativity and cosmology

Starting with the idea that the inertia of bodies is a general property of all kinds of their potential energy, the author arrives at the two fundamental megaphysical equations (I, II)⁰ +c²=0,⁰ =0 where⁰ is the scalar gravitational potential due to the smoothed-out universe,⁰ is its electrostatic potential andc denotes the light velocity in vacuo.The first equation means physically that the cosmic potential⁰ determines uniquely the velocity of light and consequently the pseudo-Euclidean geometry in an inertial frame, in the absence of local gravitational fields. This fact implies the validity of the law of inertia in a non-empty universe only, in full agreement with Mach's principle.If we adopt, for the cosmic potential, that of Seeliger, differing from the Newtonian potential by the exponential factor exp (–r/r_g), we can use Eq. (I) to estimate the lower limit of the range r_g of gravitational interaction within the limits (10¹⁰–10¹²) light years. This suggests a steadystate model of the universe consisting of an unlimited number of finite regions (sub-universes) oscillating independently of each other. Such a superlarge-scale model universe is in agreement with the observed galactic red shift and yet it fulfils the perfect cosmological principle.     

Long-time tails in lattice Lorentz gases

We consider a Lorentz gas on a square lattice with a fraction c of scattering sites. The collision laws are deterministic (fixed mirror model) or stochastic (with transmission, reflection, and deflection probabilities ,, and respectively). If all mirrors are parallel, the mirror model is exactly solvable. For the general case a self-consistent ring kinetic equation is used to calculate the longtime tails of the velocity correlation function (0) (t) and the tensor correlation Q(0)Q(t) withQ= _{x y} . Both functions showt ^–2 tails, as opposed to the continuous Lorentz gas, where the tails are respectivelyt ^–2 andt ^–3. Inclusion of the self-consistent ring collisions increases the low-density coefficient of the tail in (0)(t) by 30–100% as compared to the simple ring collisions, depending on the model parameters.     

A structurally diverse heterocyclic library: A benzothiazepine-fused β -lactam library derived from reaction of 2,3-dihydro-1,5-benzothiazepines and acyl chlorides: Synthesis and stereochemistry

A 1H-azeto[2,1-d][1,5]benzothiazepin-1-one, -lactam derivatives of dihydrobenzothiazepines library derived from reactions of 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines and acyl chlorides, including phthalimidoacetyl chloride, chloroacetyl chloride, dichloroacetyl chloride and phenoxyacetyl chloride, was built up through parallel solution-phase synthesis. Stereochemistry of 1H-azeto[2,1-d][1,5]benzothiazepin-1-ones in the reaction process is discussed.     

Unstable Particles, Gauge Invariance and the Δ++ Resonance Parameters

The elastic and radiative ⁺ p scattering are studied in the framework of an effective Lagrangian model for the ⁺⁺ resonance and its interactions. The finite width effects of this spin-3/2 resonance are introduced in the scattering amplitudes through a complex mass scheme to respect electromagnetic gauge invariance. The resonant pole ( ⁺⁺) and background contributions ( ⁰, , , and neutron states) are separated according to the principles of the analytic S-matrix theory. The mass and width parameters of the ⁺⁺ obtained from a fit to experimental data on the total cross section are in agreement with the results of a model-independent analysis based on the analytic S-matrix approach. The magnetic dipole moment determined from the radiative ⁺ p scattering is nuclear magnetons.     

Some investigations of inductive properties of forward biased selenium rectifiers

Investigations of the inductive properties of forward biased rectifiers have revealed thatC ^– (which characterizes inductance) is a linear function of 1/f ² and 1/R ². If an a.c. voltage of small amplitude is applied to such a rectifier, the amplifier behaves like a parallel resonant circuit of lowQ. The resonant frequency of such a circuit increases linearly with increasing forward current.On leave from the State University, Takent, USSR.The author wishes to express her gratitude to Dr. V. anderová, J. Kode and K. Vavina for the attention they have devoted to this paper and for their evaluation of the results.     

Kinetic limits of the HPP cellular automaton

We study the Boltzmann-Grad limit in various versions of the two-dimensional HPP cellular automaton. In the completely deterministic case we prove convergence to an evolution that is not of kinetic type, a well-known phenomenon after Uchyiama's paper on the Broadwell gas, whereas the limiting equation becomes of kinetic type in the model with random collisions. The main part of the paper concerns the case where the collisions are deterministic and the randomness comes from inserting, between any two successive HPP updatings, ^- stirring updatings, <1 being any fixed positive number and a parameter which tends to 0. The initial measure is a product measure with average occupation numbers of the order of (low-density limit) and varying on distances of the order of ^–1. The limit as 0 of the system evolved for times of the order of ^-1- corresponds to the Boltzmann-Grad limit. We prove propagation of chaos and that the renormalized average occupation numbers (i.e., divided by) converge to the solution of the Broadwell equation. Convergence is proven at all times for which the solution of the Broadwell equation is bounded.     

On the tensor product of supersingleton representations ofosp(1, 2n)

The tensor product of two supersingleton representations _n of the Lie superalgebraosp (1, 2n) is studied forn2. The main results are as follows: (a) anticommutators and commutators of the odd generators in _{n n} form a skew-symmetric representation of the Lie algebrau(n, n); (b) simple explicit form of all irreducible components of _{n n}, which are labelled by a single parameterJ=0, 1, ..., has been found. Each of them is a^*-representation ofosp (1, 2n) for which assertion (a) is valid. The dimension of its vacuum subspace equals , i.e., the nondegenerate vacuum occurs for J=0 only. Basic property of this family of irreducible^*-representations of osp(1, 2n) are analogous to those of massless representations of osp(1, 4).Dedicated to Academician Václav Votruba on the occasion of his eightieth birthday.     

Magnetic field alignment of high-T c superconductorsRBa2Cu3O7–δ (R=rare earth)

Finely ground powders ofRBa₂Cu₃O_{7 –} (R=Y, Nd, Sm, Eu, Dy, Ho, Er, Tm, Yb) have been mixed at dilute 3%-by-volume concentrations into epoxy matrices which were then allowed to harden in applied magnetic fieldsH _A=18 kOe. X-ray diffractometry studies and 4.3 K measurements of supercurrent-induced magnetization hysteresisM are interpreted as indicating at least partial alignment of single-crystal-grain c-axes (1) parallel toH _A forR=Y, Nd, Sm, Dy, Ho (as earlier found by Farrell et al. forR=Y), and (2) perpendicular toH _A forR=Eu, Er, Tm, Yb. With a few exceptions (Y, Sm, Eu) the alignment direction correlates with the sign of the second-order Stevens factor _J of the crystalline electric field Hamiltonian in the manner suggested by Livingston et al. For the best aligned specimens (Ho, Dy) critical current densitiesJ _c (4.3 K, 5 kOe) for individual grains are estimated fromM and the Bean model to be of order 10⁷ A/cm² for the measuring fieldH parallel to the original alignment fieldH _A, and of order 10⁶ A/cm² forH perpendicular toH _A.     

Translation group and spectrum condition

Let {A, ^d ,} be aC*-dynamical system, where ^d is thed-dimensional vector group. LetV be a convex cone in ^d and its dual cone. We will characterize those representations ofA with the properties (i) _a ,a ^d is weakly inner, (ii) the corresponding unitary representationU(a) is continuous, and (iii) the spectrum ofU(a) is contained in .     

Superconformal Symmetry and HyperKähler Manifolds with Torsion

The geometry arising from Michelson & Strominger's study of =4B supersymmetric quantum mechanics with superconformal D(2, 1; )-symmetry is a hyperKähler manifold with torsion (HKT) together with a special homothety. It is shown that different parameters are related via changes in potentials for the HKT target spaces. For 0, –1, we describe how each such HKT manifold M ^4m is derived from a space N ^4m–4 which is quaternionic Kähler with torsion and carries an Abelian instanton.     

Ising Models on Hyperbolic Graphs II

We consider Ising models with ferromagnetic interactions and zero external magnetic field on the hyperbolic graph (v, f), where v is the number of neighbors of each vertex and f is the number of sides of each face. Let T _c be the critical temperature and T _c =supTT _c: ^f=( ⁺+ ^–)/2, where ^f is the free boundary condition (b.c.) Gibbs state, ⁺ is the plus b.c. Gibbs state and ^– is the minus b.c. Gibbs state. We prove that if the hyperbolic graph is self-dual (i.e., v=f) or if v is sufficiently large (how large depends on f, e.g., v35 suffices for any f3 and v17 suffices for any f17) then 0<T _c <T _c, in contrast with that T _c =T _c for Ising models on the hypercubic lattice Z ^d with d2, a result due to Lebowitz.⁽²²⁾ While whenever T<T _c , ^f=( ⁺+ ^–)/2. The last result is an improvement in comparison with the analogous statement in refs. 28 and 33, in which it was only proved that ^f=( ⁺+ ^–)/2 when TT _c and it remains to show in both papers that ^f =( ⁺+ ^–)/2 whenever T<T _c . Therefore T _c and T _c divide [0, ] into three intervals: [0, T _c ), (T _c , T _c), and (T _c, ] in which ^{+ –} but ^f =( ⁺+ ^–)/2, ^{+ –} and ^f ( ⁺+ ^–)/2, and ⁺= ^–, respectively.     

Asymptotic behavior of the density for two-particle annihilating exclusion

We consider a stochastic process which presents an evolution of particles of two types,A andB, onZ ^d with annihilations between particles of opposite types. Initially, at each site ofZ ^d, independently of the other sites, we put a particle with probability 2<1 and assign to it one of two types with equal chances. Each particle evolves onZ ^d in the following manner: independently from the others, it waits an exponential time with mean 1, chooses one of its neighboring sites on the latticeZ ^d with equal probabilities, and jumps to the site chosen. If the site to which a particle attempts to move is occupied by another particle of the same type, the jump is suppressed; if it is occupied by a particle of the opposite type, then both are annihilated and disappear from the system. The considered process may serve as a model for the chemical reactionA+Binert. Let (t) denote the density of particles in this process at timet. We prove that there exist absolute finite constantsc(d) andC(d) such that for all sufficiently larget,c(d)t ^–d/4 (t)C(d)t ^–d/4 in the dimensionsd4 andc(d)t ^–1 (t)C(d)t ^–1 in all higher dimensions. This completes and makes more precise the results obtained by us earlier and shows that asymptotically the density behaves like that in a similar process called two-particle annihilating random walks which was studied by Bramson and Lebowitz. Our proofs are based on the approach developed in their and our works. We use the basic properties of random walk and various tools which have been designed to study simple symmetric exclusion processes.     

Solid-phase synthesis of model libraries of 3 α17β-dihydroxy-16α-(aminoethyl-N-substituted)-5α-androstanes for the development of steroidal therapeutic agents

The solid-phase synthesis of 16-derivatives of 5-androstane-3,17-diol with one, two or three levels of molecular diversity was accomplished using the diethylsilyloxy linker. Libraries with one level of diversity (10 members) and two levels of diversity (40 members) were synthesized in a parallel fashion in good yields and acceptable HPLC purities for the majority of library members. Compounds with three levels of diversity (15 pools) were realized in a split and pool fashion to allow further deconvolution by the positional scanning method. The screening of the generated model libraries revealed interesting preliminary structure–activity relationships related to their antiproliferative activities on androgen-sensitive Shionogi cells. In the case of the two-level library, the presence of a hydrophobic amino acid at R₁ (isoleucine (Ile) or phenylalanine (Phe)) and a six-membered ring (aromatic or not) at R₂ seems an important requirement for activity. In the three-level library, the amino acid residues isoleucine and phenylalanine clearly provided a better antiproliferative activity than glycine (Gly) and proline (Pro). These model libraries will serve as basis for the generation of larger libraries of peptidosteroids toward the development of therapeutic agents.