Polymeric photosensitizer prodrugs for photodynamic therapy

A targeting strategy based on the selective enzyme-mediated activation of polymeric photosensitizer prodrugs (PPP) within pathological tissue has led to the development of agents with the dual ability to detect and treat cancer. Herein, a detailed study of a simple model system for these prodrugs is described. We prepared "first-generation" PPP by directly tethering the photosensitizer (PS) pheophorbide a to poly-(L)-lysine via epsilon amide links and observed that by increasing the number of PS on a polymer chain, energy transfer between PS units improved leading to better quenching efficiency. Fragmentation of the PPP backbone by trypsin digestion gave rise to a pronounced fluorescence increase and to more efficient generation of reactive oxygen species upon light irradiation. In vitro tests using the T-24 bladder carcinoma cell line and ex vivo experiments using mouse intestines illustrated the remarkable and selective ability of these PPP to fluoresce and induce phototoxicity upon enzymatic activation. This work elucidated the basic physicochemical parameters, such as water solubility and quenching/activation behavior, required for the future elaboration of more adaptable "second-generation" PPP, in which the PS is tethered to a proteolytically stable polymer backbone via enzyme-specific peptide linkers. This polymer architecture offers great flexibility to tailor make the PPP to target any pathological tissue known to over-express a specific enzyme.     

Understanding the chemical reactivity of phenylhalocarbene systems: an analysis based on the spin-polarized density functional theory

Global and local indices based on the spin-polarized density functional theory (SP-DFT) have been used to rationalize the philicity power and spin polarization pattern of a family of singlet substituted phenylhalocarbenes, (pYPhXC, Y = –NO₂ , –CN, –CHO, –F, –H, –CH₃ , –OH, –OCH₃ , –NH₂ ; X = –F, –Cl, –Br). The local reactivity may be traced out by the simple condensed-to-atoms model for the SP-DFT Fukui functions, namely and . For the addition of some singlet phenylhalocarbenes on tetramethylethylene a linear correlation among the global and local electrophilicity index , and the observed rate constants were found. This result supports a mechanistic model where the carbene adds to the olefin in a single step that is controlled by the carbene electrophilicity. These results emphasize the usefulness of general SP-DFT philicities in the rationalization of chemical reactivity at initial stages of reactions that could involve both charge transfer and spin polarization processes.     

Asymmetric synthesis of (+)-mequitazine from quinine

The first asymmetric synthesis of the antihistaminic drug mequitazine is reported. Our approach started from quinine, a Cinchona alkaloid, whose chiral information was exploited for setting up the stereogenic center of (+)-mequitazine.     

A comparative study of fragment screening methods on the p38�� kinase: new methods, new insights

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(?) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(?)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.     

Molecular recognition at the active site of catechol-O-methyltransferase (COMT): adenine replacements in bisubstrate inhibitors

L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrüggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC(50) values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg(2+) confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group.     

Vitrifying star-shaped liquid crystals: synthesis and application in cholesteric polymer networks

In this paper, the formation of glass-forming reactive mesogens, that do not crystallize upon cooling, but vitrify and form supercooled LC phases, is described. These molecules exhibit broad range LC phases and enable us to carry out photopolymerization in a broad range of temperatures. From such reactive mesogens densely crosslinked networks in which the liquid crystalline order is permanently fixed are formed by photopolymerization. For this purpose eight novel low molecular mass LC materials with photopolymerizable acrylate groups have been synthesized and the detailed experimental procedures are given. The molecules have a star-shaped topology with three and four arms. The mesogenic units were varied by the addition of lateral groups in different positions. Comparing the twin molecules which we have described before with the novel three- and four-armed stars, we found that the supercooled LC phase in the three-armed stars has a stability superior to that in both twin molecules and four-armed stars. In the three-armed star triple-4 with a suitable substituent pattern, the supercooled nematic phase is stable at room temperature for at least nine months. Photo-DSC experiments show that the final conversion after 10 min of UV-irradiation for the threearmed star molecule triple-4 is as high as for the smaller molecules twin-4 and mono-4 over the whole temperature range. Doped with a suitable chiral molecule the novel nematics formed cholesteric phases which were used to make cholesteric polymer networks by photopolymerization.     

1,6-Anhydrofurawosen,XX.1 Synthese von Zuei 1,6:2,3-Dianhydrohexofuranosen Durch Payne-Oxidation von 1,6-Anhydro-5-O-Benzoyl-2,3-Didesoxy-β-D-Erythro- uno -α-L-Threo-Hex-2-Enofuranose

Abstract

The 5-0-benzoyl derivatives 3 and 4 derived from 1,6-anhydro-β-D-mannpfuranose and -α-L-gulofuranose are suitable educts for the preparation of the isomeric olefins 7 and 8 by Corey-Winter elimination via the thionocarbonates 5 and 6, respectively. 8 was prepared in higher yields also from 5-α-Benzoyl-1,6-anhydro-α-L-talofuranose (14) via 15. Payne oxidation of the unsaturated compounds 7 and 8 gave the exo epoxides 9 and 10 with D-allo and L-talo configuration.     

SModelS: a tool for interpreting simplified-model results from the LHC and its application to supersymmetry

We present a general procedure to decompose Beyond the Standard Model (BSM) collider signatures presenting a $\mathbb {Z}_2$ symmetry into Simplified Model Spectrum (SMS) topologies. Our method provides a way to cast BSM predictions for the LHC in a model independent framework, which can be directly confronted with the relevant experimental constraints. Our concrete implementation currently focusses on supersymmetry searches with missing energy, for which a large variety of SMS results from ATLAS and CMS are available. As show-case examples we apply our procedure to two scans of the minimal supersymmetric standard model. We discuss how the SMS limits constrain various particle masses and which regions of parameter space remain unchallenged by the current SMS interpretations of the LHC results.