Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens

BACKGROUND: The development of estrogen pharmaceutical agents with appropriate tissue-selectivity profiles has not yet benefited substantially from the application of combinatorial synthetic approaches to the preparation of structural classes that are known to be ligands for the estrogen receptor (ER). We have developed an estrogen pharmacophore that consists of a simple heterocyclic core scaffold, amenable to construction by combinatorial methods, onto which are appended 3-4 peripheral substituents that embody substructural motifs commonly found in nonsteroidal estrogens. The issue addressed here is whether these heterocyclic core structures can be used to prepare ligands with good affinity for the ER. RESULTS: We prepared representative members of various azole core structures. Although members of the imidazole, thiazole or isoxazole classes generally have weak binding for the ER, several members of the pyrazole class show good binding affinity. The high-affinity pyrazoles bear close conformational relationship to the nonsteroidal ligand raloxifene, and they can be fitted into the ligand-binding pocket of the ER-raloxifene X-ray structure. CONCLUSIONS: Compounds such as these pyrazoles, which are novel ER ligands, are well suited for combinatorial synthesis using solid-phase methods.     

Uniform factorization for compact sets of operators

We prove a factorization result for relatively compact subsets of compact operators using the Bartle and Graves Selection Theorem, a characterization of relatively compact subsets of tensor products due to Grothendieck, and results of Figiel and Johnson on factorization of compact operators. A further proof, essentially based on the Banach-Dieudonné Theorem, is included. Our methods enable us to give an easier proof of a result of W.H. Graves and W.M. Ruess.

     

Regularity and Algebras of Analytic Functions in Infinite Dimensions

A Banach space is known to be Arens regular if every continuous linear mapping from to is weakly compact. Let be an open subset of , and let denote the algebra of analytic functions on which are bounded on bounded subsets of lying at a positive distance from the boundary of We endow with the usual Fréchet topology. denotes the set of continuous homomorphisms . We study the relation between the Arens regularity of the space and the structure of .

     

Separation Theorems for Group Invariant Polynomials

We study the existence of separation theorems by polynomials that are invariant under a group action. We show that if G is a finite subgroup of \(\textit{GL}(n,{\mathbb {C}})\), K is a set in \({\mathbb {C}}^{n}\) that is invariant under the action of G and z is a point in \({\mathbb {C}}^{n}\setminus K\) that can be separated from K by a polynomial Q, then z can be separated from K by a G-invariant polynomial P. Furthermore, if Q is homogeneous then P can be chosen to be homogeneous. As a particular case, if K is a symmetric polynomially convex compact set in \({\mathbb {C}}^{n}\) and \(z\notin K\) then there exists a symmetric polynomial that separates z and K.     

The Bishop-Phelps-Bollobás theorem for operators

We prove the Bishop-Phelps-Bollobás theorem for operators from an arbitrary Banach space X into a Banach space Y whenever the range space has property β of Lindenstrauss. We also characterize those Banach spaces Y for which the Bishop-Phelps-Bollobás theorem holds for operators from ?₁ into Y. Several examples of classes of such spaces are provided. For instance, the Bishop-Phelps-Bollobás theorem holds when the range space is finite-dimensional, an L₁(μ)-space for a σ-finite measure μ, a C(K)-space for a compact Hausdorff space K, or a uniformly convex Banach space.     

Stereochemistry of post-transition metal oxides: revision of the classical lone pair model

The chemistry of post transition metals is dominated by the group oxidation state N and a lower N-2 oxidation state, which is associated with occupation of a metal s(2) lone pair, as found in compounds of Tl(I), Pb(II) and Bi(III). The preference of these cations for non-centrosymmetric coordination environments has previously been rationalised in terms of direct hybridisation of metal s and p valence orbitals, thus lowering the internal electronic energy of the N-2 ion. This explanation in terms of an on-site second-order Jahn-Teller effect remains the contemporary textbook explanation. In this tutorial review, we review recent progress in this area, based on quantum chemical calculations and X-ray spectroscopic measurements. This recent work has led to a revised model, which highlights the important role of covalent interaction with oxygen in mediating lone pair formation for metal oxides. The role of the anion p atomic orbital in chemical bonding is key to explaining why chalcogenides display a weaker preference for structural distortions in comparison to oxides and halides. The underlying chemical interactions are responsible for the unique physicochemical properties of oxides containing lone pairs and, in particular, to their application as photocatalysts (BiVO(4)), ferroelectrics (PbTiO(3)), multi-ferroics (BiFeO(3)) and p-type semiconductors (SnO). The exploration of lone pair systems remains a viable a venue for the design of functional multi-component oxide compounds.     

Divalent metal complexes (Ca, Sr, Ba, Yb) of the unsymmetrical 3-(2'-thienyl)-5-(trifluoromethyl)pyrazolate ligand

The divalent complexes [M(ttfpz)(2)(thf)(4)] (ttfpz = 3-(2'-thienyl)-5-(trifluoromethyl)pyrazolate; M = Yb, 1, Ca, 2, Sr, 3, Ba, 4; thf = tetrahydrofuran) and [M(ttfpz)(2)(dme)(n)] (M = Ca, 5, Sr, 6, Yb, 7, n = 2; M = Ba, 8, n = 3; dme = 1,2-dimethoxyethane) have been prepared by redox transmetallation/protolysis reactions employing the free metals, Hg(C(6)F(5))(2) and ttfpzH in donor solvents and their structures determined. The monomeric structures exhibit η(2)-bound pyrazolate ligands with eight-coordinate metal atoms for complexes 1-7 and a ten-coordinate metal for 8. The pyrazolate ligands in the thf-complexes 1-4 as well as dme-derivatives 5 and 6 are in a transoid configuration, whilst in complex 7 the ttfpz ligands exhibit a cisoid relationship. In 8 the ligands have an intermediate role in between cisoid and transoid.