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Synthesis

Meeting Briefs

November 13, 2006 | APPEARED IN VOLUME 84, ISSUE 46

C&EN attended the annual meetings of the Swiss Academy of Sciences and the Swiss Chemical Society, held jointly in Zurich on Oct. 12-13. Here's a sampling of the research presented there.

Siderophore-Anchored Polymer Beats Biofouling

A polymer coating held in place with a metal chelator may be just the trick to prevent proteins and other biomolecules from sticking to medical implants. To anchor protein-resistant poly(ethylene glycol) (PEG) to a titanium dioxide surface, Karl Gademann used siderophores as inspiration. These natural products have been evolutionarily optimized to bind iron and as such present excellent starting points for designing anchors that can attach functional molecules to metal surfaces, he said. Gademann, an assistant professor of chemistry at the Swiss Federal Institute of Technology, Lausanne, and his team conjugated a fragment of the cyanobacterial siderophore anachelin to PEG. This conjugate (shown) forms a stable monolayer on titanium dioxide surfaces (J. Am. Chem. Soc. 2006, 128, 1064). Human serum does not adhere to surfaces coated in this way, Gademann reported. Zurich-based SurfaceSolutions plans to commercialize the coatings for use in biomedical devices.

Molecule Regulates Cell Trafficking

A cyclized peptidelike molecule could help cancer patients rebuild their immune systems following therapy, according to Alexander Lederer of Polyphor, in Allschwil, Switzerland. Polyphor, in collaboration with John A. Robinson of the University of Zurich, designs small molecules that mimic the surfaces of disease-associated proteins engaged in protein-protein interactions. Lederer described the company's efforts to craft a molecule that blocks the action of the chemokine receptor protein CXCR4, a cell-surface protein that regulates trafficking of many kinds of cells, including stem cells, through specific protein-protein interactions. His team used the β-hairpin-shaped natural product polyphemusin II, one of the first known CXCR4 antagonists, as a starting point for the design of libraries of cyclic, peptidelike CXCR4 antagonists (Bioorg. Med. Chem., DOI: 10.1016/j.bmc.2006.09.003). Optimization of the most promising hit gave POL3026, which induces mobilization and colonization of stem cells in mice, he noted. The company hopes the compound will prove useful for facilitating the harvesting of stem cells from cancer patients' blood that can later be used to rebuild their immune systems following chemo- or radiation therapy, Lederer said.

Alcohols Reduce Radicals

Alcohols and water complexed to boron derivatives are promising and mild alternatives to toxic tin-based radical-reducing reagents in radical reactions, reported Davide Pozzi of the University of Bern, Switzerland. Pozzi and Philippe Renaud previously reported that alkyl radicals, generated by decomposition of B-alkylcatecholboranes, can be reduced with catecholborane-methanol complexes. Typically, such radical reactions rely on toxic tin species to reduce radicals. The use of tin has been seen as a roadblock to the commercial use of radical reactions, Pozzi said, and organoboranes "are a promising metal-free alternative." He described how organoboron complexes containing methanol, other alcohols, and even water can be used as mild reducing agents in other radical reactions, including the reduction of halides. As in the published reaction, the O-H bond of the alcohol complexed by the borane compound delivers the hydrogen atom. The observations "offer new opportunities for the design of novel tin-free radical- reducing agents," Pozzi said.

Introducing The Azathilones

A new structural scaffold inspired by the epothilones, a class of microtubule-stabilizing natural products now undergoing clinical evaluation, may have a distinct and useful pharmacological profile. Fabian Feyen of the Swiss Federal Institute of Technology (ETH), Zurich, described the conception and synthesis of the azathilones, which share a macrolactone ring with natural epothilones but not much else. Feyen and Karl-Heinz Altmann of ETH have constructed several substituted azathilones via either ring-closing olefin metathesis or macrolactonization (Angew. Chem. Int. Ed. 2006, 45, 5880). All of the compounds are highly potent inhibitors of human tumor growth in vitro, with the azathilone shown above stacking up to the natural product epothilone A in both antitumor activity and tubulin polymerization, Feyen reported. "The azathilones should thus be attractive new lead structures for anticancer drug discovery," he noted.

Tuning Electron Transfer

The quest to understand quantitatively how small changes to molecular networks affect biological electron-transfer rates may be aided by the computational efforts of Joost VandeVondele of the University of Zurich. In cellular processes such as photosynthesis, each electron-transfer step is carried out in a protein environment that's been exquisitely optimized for that particular task. Hoping to better explain the role hydrogen bonding plays in tuning such electron-transfer rates, VandeVondele and coworkers investigated the redox properties of substituted quinones in methanol, which supports hydrogen-bonding interactions, versus in acetonitrile, which does not (Angew. Chem. Int. Ed. 2006, 45, 1936). Combining molecular dynamics simulations and density functional theory allowed the researchers to rationalize how chemical substituents and environmental changes affect the redox potentials and reorganization energies of quinones, VandeVondele noted. He said the approach should allow "further exploration of the redox properties of systems of biological interest in their native environment."

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