Attractive in theory and confirmed to exist, anion-pi interactions have never really been seen at work. To catch them in action, we prepared a collection of monomeric, cyclic and rod-shaped naphthalenediimide transporters. Their ability to exert anion-pi interactions was demonstrated by electrospray tandem mass spectrometry in combination with theoretical calculations. To relate this structural evidence to transport activity in bilayer membranes, affinity and selectivity sequences were recorded. pi-acidification and active-site decrowding increased binding, transport and chloride > bromide > iodide selectivity, and supramolecular organization inverted acetate > nitrate to nitrate > acetate selectivity. We conclude that anion-pi interactions on monomeric surfaces are ideal for chloride recognition, whereas their supramolecular enhancement by pi,pi-interactions appears perfect to target nitrate. Chloride transporters are relevant to treat channelopathies, and nitrate sensors to monitor cellular signaling and cardiovascular diseases. A big impact on organocatalysis can be expected from the stabilization of anionic transition states on chiral pi-acidic surfaces.

The objective of this Feature Article is to reflect on the importance of established and emerging principles of supramolecular organic chemistry to address one of the most persistent problems in life sciences. The main topic is dynamic covalent chemistry on cell surfaces, particularly disulfide exchange for thiol-mediated uptake. Examples of boronate and hydrazone exchange are added for contrast, comparison and completion. Of equal importance are the discussions of proximity effects in polyions and counterion hopping, and more recent highlights on ring tension and ion pair-π interactions. These lessons from supramolecular organic chemistry apply to cell-penetrating peptides, particularly the origin of "arginine magic" and the "pyrenebutyrate trick," and the currently emerging complementary "disulfide magic" with cell-penetrating poly(disulfide)s. They further extend to the voltage gating of neuronal potassium channels, gene transfection, and the delivery of siRNA. The collected examples illustrate that the input from conceptually innovative chemistry is essential to address the true challenges in biology beyond incremental progress and random screening.

This critical review covers progress with synthetic transport systems, particularly ion channels and pores, between January 2006 and December 2009 in a comprehensive manner. This is the third part of a series launched in the year 2000, covering a rich collection of structural and functional motifs that should appeal to a broad audience of non-specialists, including to organic, biological, supramolecular and polymer chemists. Impressive breakthroughs have been achieved over the past four years in part because of a fruitful expansion toward new types of interactions, including metal-organic, π-π, aromatic electron donor-acceptor, anion-π or anion-macrodipole interactions as well as dynamic covalent bonds (169 references).

The delivery of materials for genetic engineering with transitory activity constitutes a promising field in biology and medicine with potential applications in the treatment of disease, from cancer and infectious diseases to inheritable disorders. The possibility to restore the expression of a missing protein, the potential correction of the splicing of defective genes, or the silencing or modulation of the expression of other genes constitute powerful tools that will have a great impact in the future of biology and medicine. Impressive progress has been made in the last decade, with several products reaching the market as novel technologies for gene editing emerge. However, the transference of these technologies to functional therapies is hindered by the suboptimal performance of vehicles in capturing, protecting and delivering the corresponding nucleotide cargoes with safety and efficacy.Chemistry and the chemical sciences will play a key role in the development of the innovative synthetic materials that will overcome the upcoming challenges of the next generation gene delivery therapies and protocols. In this review we address the newest chemical advances in the production of materials at the forefront of nucleotide cell delivery and gene therapy.