Organic Chemistry at the Interface to Biology

Abstract

The continued development of new reactions, reagents and analytical tools within organic chemistry has increased the power and control of how organic and in particular bioorganic molecules may be transformed, modified and studied. The way researchers use synthetic and natural chemical entities, as well as the chemical modification of biological entities, has undergone a true revolution to reveal mechanisms, pathways and therapeutic interventions in a plethora of biological systems. Thus, an expanding independent field at the interface between chemistry and biology, including bioorganic chemistry, medicinal chemistry and chemical biology, has been emerging over many years. On the 27th and 28th of January at the Falconer Center in Copenhagen, Denmark, 200 researchers from industry and academia gathered for the 4th Knud Lind Larsen symposium entitled “Organic Chemistry at the Interface to Biology” to hear prominent researchers in the field present their work. These two-day symposia, held every second year by The Danish Academy of Technical Sciences (www.atv.dk), are the most prestigious international chemistry meeting in Denmark and cover various aspects of organic chemistry. The symposium has a different theme each time and a tradition of attracting very prominent speakers. The meeting also hosts the presentation of the Knud Lind Larsen Prize, which is given to a talented young Danish chemist. This year, the prize was presented by the Danish Minister for Science, Technology and Innovation, Helge Sander, to Frederik Christian Krebs from the Riso National Laboratory in Denmark (www.risoe.dk). Krebs was awarded for his research in polymer-based organic solar cells. In his prize lecture, Krebs stated that his personal mission was to put plastic solar cells on the market. However, stability and efficiency problems counteract this, though low cost compared to conventional inorganic solar cells should be guaranteed. Initial stability problems, primarily caused by oxygen, have now been solved, and the prize winner was confident that eventually the efficiency problem would be solved, too. As later stated by Professor Shinkai, organic chemistry potentially can introduce more variation than inorganic chemistry, and therefore the potential could be greater. During the work, Krebs and coworkers devised an efficient method for removing Pd from their final product, a well-known problem for most Pd-coupling reactions. The first step in putting solar cells on the market was a collaboration with designers to make clothes containing the solar cells. The symposium was opened by Professor Klaus M;ller, from F. Hoffman–La Roche, who discussed why benzodiazepines are privileged in drug development, and concluded that the sevenmembered carboand heterocyclic ring structure offers privileged structures, in general. An extensive search in the Cambridge Structural Database (CSD) revealed that, depending on the number of unsaturated bonds in the ring, various stabilised conformations are obtained that point the ring substituents in defined directions. Thus, the seven-membered ring system, as opposed to fiveand six-membered rings, is a treasury offering excellent conformationally restricted scaffolds. Furthermore, another privileged structure, sulfonamide, was investigated for its ability to accept hydrogen bonds. Again, an extensive search in the CSD revealed that the oxo-groups of sulfonACHTUNGTRENNUNGamides rarely participate in hydrogen bonds, but rather display dipole interactions with amide carbonyl groups; this explains why this is a popular functional group. Project leader from Pfizer David Price gave the audience a clear impression of the tremendous efforts underlying the discovery of Maraviroc (UK-427857), an antagonist at the CCR5 chemokine receptor that is applied in the treatment of HIV infections. The target was originally established from the notion that homozygous people with a mutation in the CCR5 coreceptor were resistant to the HIV virus, whereas heterozygotes displayed a delayed disease progression. Starting from a hit in a high-throughput screening, many of the problems with respect to affinity, antiviral potency, HERG channel activity, absorption, degradation, etc. were solved through a series of functional-group interchanges, conformational restrictions and bioisosteric exchanges. And as often observed in medicinal chemistry, solving one problem creates another, but eventually they arrived at Maraviroc, which had all the desired properties, including a very slow off-rate, which is probably necessary for the drug to prohibit the initial virus binding. Professor Tom W. Muir, from the Rockefeller University, has for several years shown how expressed protein ligation (EPL) can be used to incorporate novel functions into natural proteins in order to understand crucial mechanisms and pathways. The technology exploits the natural extein–intein system for protein ligation, and in his lecture, several examples convincingly displayed the power of this technique. The first application was in the TGF-b signalling pathway, in which activation by phosphorylation of [a] Prof. Dr. R. P. Clausen Department of Medicinal Chemistry Danish University of Pharmaceutical Sciences Universitetsparken 2 2100 Copenhagen (Denmark) Fax: (+45)3530-6040 E-mail : rac@dfuni.dk [**] Report on the Knud Lind Larsen Symposium.