closo-borane conjugated regulatory peptides retain high biological affinity: synthesis of closo-borane conjugated Tyr(3)-octreotate derivatives for BNCT

Despite the improvements in cancer therapy during the past years, high-grade gliomas and many other types of cancer are still extremely resistant to current forms of therapy. Boron neutron capture therapy (BNCT) provides a promising way to destroy cancer cells without damaging healthy tissue. However, BNCT in practice is still limited due to the lack of boron-containing compounds that selectively deliver boron to cancer cells. Since many neuroendocrine tumors show an overexpression of the somatostatin receptor, it was our aim to synthesize compounds that contain a large number of boron atoms and still show high affinity toward this transmembrane receptor. The synthetic peptide Tyr (3)-octreotate (TATE) was chosen as a high-affinity and internalizing tumor targeting vector (TTV). Novel boron cluster compounds, containing 10 or 20 boron atoms, were coupled to the N-terminus of TATE. The obtained affinity data demonstrate that the use of a spacer between TATE and the closo-borane moiety is the option to avoid a loss of biological affinity of closo-borane conjugated TATE. For the first time, it was shown that closo-borane conjugated regulatory peptides retain high biological affinity and selectivity toward their transmembrane tumor receptors. The results obtained and the improvement of spacer and boron building block chemistry may stimulate new directions for BNCT.

Synthesis and SAR of C12-C13-oxazoline derivatives of epothilone A

The SAR of a series of new epothilone A derivatives with a 2-substituted-1,3-oxazoline moiety trans-fused to the C12-C13 bond of the deoxy macrocycle have been investigated with regard to tubulin polymerization induction and cancer cell growth inhibition. Significant differences in antiproliferative activity were observed between different analogs, depending on the nature of the substituent at the 2-position of the oxazoline ring. The most potent compounds showed comparable activity with the natural product epothilone A. Modeling studies provide a preliminary rationale for the observed SAR.

Benzamidine derivatives inhibit the virulence of Porphyromonas gingivalis

We have previously shown that benzamidine-type compounds can inhibit the activity of arginine-specific cysteine proteinases (gingipains HRgpA and RgpB); well-known virulence factors of Porphyromonas gingivalis. They also hinder in vitro growth of this important periodontopathogenic bacterium. Apparently growth arrest is not associated with their ability to inhibit these proteases, because pentamidine, which is a 20-fold less efficient inhibitor of gingipain than 2,6-bis-(4-amidinobenzyl)-cyclohexanone (ACH), blocked P. gingivalis growth far more effectively. To identify targets for benzamidine-derived compounds other than Arg-gingipains, and to explain their bacteriostatic effects, P. gingivalis ATCC 33277 and P. gingivalis M5-1-2 (clinical isolate) cell extracts were subjected to affinity chromatography using a benzamidine-Sepharose column to identify proteins interacting with benzamidine. In addition to HRgpA and RgpB the analysis revealed heat-shock protein GroEL as another ligand for benzamidine. To better understand the effect of benzamidine-derived compounds on P. gingivalis, bacteria were exposed to benzamidine, pentamidine, ACH and heat, and the expression of gingipains and GroEL was determined. Exposure to heat and benzamidine-derived compounds caused significant increases in GroEL, at both the mRNA and protein levels. Interestingly, despite the fact that gingipains were shown to be the main virulence factors in a fertilized egg model of infection, mortality rates were strongly reduced, not only by ACH, but also by pentamidine, a relatively weak gingipain inhibitor. This effect may depend not only on gingipain inhibition but also on interaction of benzamidine derivatives with GroEL. Therefore these compounds may find use in supportive periodontitis treatment.

Multiasset Derivatives and Joint Distributions of Asset Prices

Several of multiasset derivatives like basket options or options on the weighted maximum of assets exhibit the property that their prices determine uniquely the underlying asset distribution. Related to that the question how to retrieve this distributions from the corresponding derivatives quotes will be discussed. On the contrary, the prices of exchange options do not uniquely determine the underlying distributions of asset prices and the extent of this non-uniqueness can be characterised. The discussion is related to a geometric interpretation of multiasset derivatives as support functions of convex sets. Following this, various symmetry properties for basket, maximum and exchange options are discussed alongside with their geometric interpretations and some decomposition results for more general payoff functions.

Correlation between Accurate Electron Density and Linear Optical Properties in Amino Acid Derivatives: L-Histidinium Hydrogen Oxalate

The accurate electron density and linear optical properties of L-histidinium hydrogen oxalate are discussed. Two high-resolution single crystal X-ray diffraction experiments were performed and compared with density functional calculations in the solid state as well as in the gas phase. The crystal packing and the hydrogen bond network are accurately investigated using topological analysis based on quantum theory of atoms in molecules, Hirshfeld surface analysis, and electrostatic potential mapping. The refractive indices are computed from couple perturbed Kohn-Sham calculations and measured experimentally. Moreover, distributed atomic polarizabilities are used to analyze the origin of the linear susceptibility in the crystal, in order to separate molecular and intermolecular causes. The optical properties are also correlated with the electron density distribution. This compound also offers the possibility to test the electron density building block approach for material science and different refinement schemes for accurate positions and displacement parameters of hydrogen atoms, in the absence of neutron diffraction data.