Doing What Comes Unnaturally– Synthetic Biomolecules

To mimic nature is a demanding but appealing task. Many metalloenzymes are difficult to isolate and purify and thus to obtain in sufficient quantities to employ in a commercially useful way. Indeed, they may not operate successfully away from their native environments. One approach is to develop synthetic compounds that mimic their chemistry. A mimic can be of two types– it may mimic the shape of the active site, or it may mimic the reaction that occurs at the active site. Arguably one might expect the former to lead to the latter but this is not usually the case, because the protein environment plays an important role in practically all enzymes.

To illustrate the art, we’ll examine a small number of shape-related synthetic examples commencing with our heme oxygen carrier. In principle if successful an artificial blood could be developed from this approach. Synthetic complexes that coordinate dioxygen are well established as the first was described by Werner and Mylius in 1898 at the very beginning of coordination chemistry. In the laboratory to mimic iron heme chemistry, two things must be achieved: oxygen coordination without iron oxidation; and removal of the opportunity for the formation of very stable dimers with-oxo linkages. This can be achieved by producing heme molecules with a scaffold on one side that prevents close approach of another heme just what the protein achieves in a different but equally elegant manner. With close approach of two iron centres prohibited in one direction and the other axial site blocked by an imidazole ligand, dimers cannot form. Initially this was achieved with what was called a ‘picket fence’ porphyrin where four bulky tert-butyl groups were disposed on one side of a synthetic porphyrin ring. A more sophisticated molecule, with a full ‘cap’ under which only a small molecule like oxygen can bind, enhanced the concept further (Figure 8.14). These are demanding organic syntheses, but their iron complexes do bind oxygen reversibly under controlled conditions indicating that the chemistry we meet in the natural heme can be reproduced to some extent with small molecule analogues. Model compounds that mimic the structure of ferredoxins can be prepared readily in the laboratory. This is achieved by choosing ligands that offer only S-donor groups, such as an R S−or chelating −S-R-S− species and forming complexes with iron, a task readily achieved in a beaker under mild conditions. Some examples appear in Figure 8.15. Mimics of carbonic anhydrase exemplify the genre further. Here a simple saturated triaza-macrocycle replaces the histidine imidazole groups of the protein yet the shape

Figure 8.14

Examples of substituted synthetic hemes as their iron (II) complexes where close face-to-face approach of another heme is forbidden by the organic scaffolds introduced (and highlighted) allowing the small dioxygen molecule to bind reversibly at the protected axial site.

Figure 8.15

Examples of Fe S, clusters synthesized in the laboratory from an iron(II) salt reacted with simple thiol ligands and sulfide ion.

around the zinc (II) is similar (Figure 8.16). Such models lack the complexity and secondary structure of 'real' systems, but allow us to gain some understanding of the way reactions and shape adaption proceed in Nature.

More extensive examples can be found in specialist texts dedicated to bioinorganic chemistry. It is not the intent to do more here than present some highlights of this increasingly important field of coordination chemistry, sufficient to represent the field and link it to the more traditional aspects of the subject.

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