Cytotoxicity and Antiproliferative Effect of Hypericin and Derivatives after Photosensitization

The toxicity on three human tumor cell lines (A431, HeLa and MCF7) of five phenanthroperylenequinones (hypericin and derivatives) and two perylenequinones (cercosporin and calphostin C) was investigated after photosensitization (4 J/cm²). Furthermore, the antiproliferative effect on HeLa cells was studied for the phenanthroperylenequinones. Hypericin, 2,5-dibromohypericin, 2,5,9,12-tetrabromohypericin and perylenequinones displayed a potent cytotoxic and antiproliferative effect in the nanomolar range. Hypericin dicarboxylic acid exhibited no photoactivity. In general, the antiproliferative activity correlated well with the photocytotoxicity. However, the nonphotocytotoxic compound hexamethylhypericin showed potent antiproliferative activity in the nanomolar range, probably exerting its action by protein kinase C inhibition. Without light irradiation, no cytotoxic and antiproliferative effect was observed for any photocytotoxic phenanthroperylenequinone compound. Furthermore, confocal laser microscopy revealed that the subcellular localization in A431 cells was similar for the photoactive compounds; the photosensitizers were mainly concentrated in the perinuclear region, probably corresponding with the Golgi apparatus and the endoplasmic reticulum. In addition, the accumulation of the photosensitizers in HeLa cells was investigated. All compounds except hypericin dicarboxylic acid were found to concentrate to a large extent in the cells. The compound 2,5,9,12-tetrabromohypericin seemed intrinsically more effective than hypericin since the intracellular concentration of the bromoderivative was a magnitude of order lower than that of hypericin although both compounds showed similar photobiological activity.     

Lewis acid double metal cyanide catalysts for hydroamination of phenylacetylene

Double metal cyanides (DMCs) are highly active recyclable heterogeneous catalysts for hydroamination of phenylacetylene with 4-isopropylaniline. The best hydroamination yields are obtained with Zn-Co DMCs, especially if the particle size is decreased by a reverse emulsion synthesis technique.     

Optimisation of gravity-fed water distribution network design: A critical review

This paper surveys the literature on the optimisation of water distribution network design. The water distribution network design (WDND) optimisation problem entails finding the material and diameter of each pipe in the network so that the total cost of the network is minimised without violating any hydraulic constraints. This is a difficult combinatorial optimisation problem, in which decision variables are discrete and both cost function and constraints are non-linear. Over the past 30 years, a large number of methods, especially in the field of (meta) heuristics, have been developed to solve this problem, most of which obtain good results on the available benchmark networks. In addition to outlining the basic features of each method, a detailed computational comparison is presented. Based on this comparison, some issues with the current state of the art in this domain are discussed, and some future research directions are suggested. Additionally, the need for an adequate set of benchmark instances is motivated, and the minimal requirements for an instance set generator are discussed.     

Ruthenocene and cyclopentadienyl pyrrolyl ruthenium as precursors for ruthenium atomic layer deposition: a comparative study of dissociation enthalpies

RuCp₂ (ruthenocene) and RuCpPy (cyclopentadienyl pyrrolyl ruthenium) complexes are used in ruthenium (Ru) atomic layer deposition (ALD) but exhibit a markedly different reactivity with respect to the substrate and co-reactant. In search of an explanation, we report here the results of a comparative study of the heterolytic and homolytic dissociation enthalpy of these two ruthenium complexes, making use of either density functional theory (DFT) or multiconfigurational perturbation theory (CASPT2). While both methods predict distinctly different absolute dissociation enthalpies, they agree on the relative values between both molecules. A reduced heterolytic dissociation enthalpy is obtained for RuCpPy compared to RuCp₂, although the difference obtained from CASPT2 (19.9?kcal/mol) is slightly larger than the one obtained with any of the DFT functionals (around 17?kcal/mol). Both methods also agree on the more pronounced stability of the Cp^? ligand in RuCpPy than in RuCp₂ (by around 9?kcal/mol with DFT and by 6?kcal/mol with CASPT2).     

Aromatic capping surprisingly stabilizes furan moieties in peptides against acidic degradation

We herein describe the synthesis of furan containing peptides for further post-synthetic derivatisation in solution through our recently developed furan-oxidation-labeling technology. Previously, it was reported by others that during acidic cleavage of furan-modified peptides, furan moieties can suffer from degradation. We demonstrate here that this degradation is position dependent and can be fully suppressed through introduction of proximate aromatic residues. Versatile introduction of 2-furylalanine at internal, C-terminal as well as the sensitive N-terminal positions has now been proven possible.     

Beta-turn modified gramicidin S analogues containing arylated sugar amino acids display antimicrobial and hemolytic activity comparable to the natural product

This paper describes the design and synthesis of gramicidin S (GS) analogues 10a-c containing arylated sugar amino acids (SAAs) as a replacement of one of the two (D)Phe-Pro beta-turn regions. The cyclic, amphiphilic peptides adopt a beta-sheet conformation featuring an unusual reverse turn induced by the SAAs. The altered turn region induces a slight distortion of the antiparallel beta-sheet, as compared to GS; the overall geometry however closely resembles that of the nonarylated GS analogue 1. GS analogues 10a-c proved to be as active as the parent GS itself as antibacterial agents and are equally efficient in lysing red blood cells. These properties are in sharp contrast to the diminished biological activity displayed by 1. We conclude that the presence of aromaticity in the turn regions of GS derivatives is required for biological activity, whereas the native conformation of the beta-hairpin is not. Our findings may guide future research toward efficient and nonhemolytic GS analogues for combating bacterial infections.