Preface

Our first volume on bioorganometallic chemistry, published in 2006, laid down some markers to underline the emergence of this multidisciplinary research field, and provided a few significant points to illustrate its early successes. It also offered a glimpse of future developments foreseeable at that time. The success of this introductory volume, whether or not it actually inspired it, certainly coincided with an explosion of organometallic synthetic biology that has exceeded our expectations. In fact, this research field is now taught in many universities and features in the most recent textbooks on general organometallic chemistry. Bioorganometallic chemistry has also taken its place among the essential topics discussed by major international organometallic chemistry conferences alongside other key areas such as catalysis.

The rapid evolution of the field, and its ability to open up new areas while continuing to delve deeper into others that are still in their early stages, has led us to believe that it would be useful to attempt an examination of current developments in the form of a second volume. For this purpose we have called upon authors whose reputations are well established, as well as some who are just setting out in new directions. This balance seems to us a faithful reflection of the current situation, where we see a strongly growing cohort of talented young researchers. The selection is based on our subjectivity, our knowledge of the field, and our reflections on its future. We have tried to focus on the new and rare, on concepts newly emerging or re-emerging, on important achievements and realistic possibilities, in order to give the reader a sense of the fundamental trends in the field. To keep the volume to a manageable size, this decision has led us to skim over or omit other aspects that have been broadly covered elsewhere in recent reviews.

Within the discipline of Chemical Biology, which is advancing on a number of fronts, the bioorganometallic subdiscipline has a unique part to play. Its medicinal aspect is particularly well represented in the literature. It is now clear that the contribution of organometallics depends on types of activity that are different from, but complementary to, those of the coordination metallodrugs whose chief target is DNA. Organometallic compounds, because of their novel three-dimensional space-filling properties, can behave as enzyme inhibitors, as Meggers has shown with kinases. The redox properties of other organometallic complexes also permit targeting of proteins, some of which have now been identified. These key points are examined from various angles.

Chapter 1, by P. Anstaett and G. Gasser, shows the importance of organometallic enzyme inhibitors from an industrial perspective. By elucidating the unique geometric and electronic properties of organometallics, the authors reveal a new set of possibilities uncovered by the quest to develop new drugs in chemical biology.

Chapter 2, by G. Jaouen et al., underlines the renewed interest in research on organometallic steroids and their ability to bind with specific receptors, where they can also act as inhibitors as, for example, in the case of the estrogen receptor. But this is a vast area, whether in terms of radiopharmaceuticals or the topic of SERMs (selective estrogen receptor modulators), for example, as demonstrated by the ferrocifens. This research may prove to be of social benefit in addressing the problems caused by endocrine disruptors, where the organometallic component is still evolving.

Chapter 3 takes up, from the novel angle of metallodrug resolution, the essential question of chirality in inorganic chemistry as instigated by Werner, which in organometallics has demonstrated its power in asymmetric synthesis. Here Romero and Sadler, aware of the importance of gaining FDA approval for "chiral switch" drugs, tackle the as yet fairly undeveloped topic of the resolution of organometallic metallodrugs and their structural stability. This seminal article is likely to be highly influential for the future.

Chapter 4, by Casini et al., focuses on the rapid development over the last few years of gold organometallics as potential metallodrugs. The unusual character of the mechanism of action is revealed, whether for complexes of Au(I) or Au(III) bound to carbenes. In particular, their antiproliferative activity is often linked to their interference in the redox homeostasis of cancer cells. These compounds also have antiparasite potential. Finally, a possible approach to their use as theranostic agents is described. These species merit the wide interest they generate.

Chapters 5-7 illustrate the potential for commercial development of a number of promising organometallics. Dubar and Biot describe in detail the mechanism of action of ferroquine, an antimalarial agent in phase II clinical trials at Sanofi Aventis. He shows that this drug can be linked to an oxidizing stress effect and plays a key role in the inhibition of the reinvasion stage of merozoites. This is an important mechanistic discovery that may provide a source of inspiration.

Romão and Vieira meanwhile take on the different aspects of the metal-carbonyl prodrugs. It is in fact known that CO is a significant biological mediator requiring controlled release to make it suitable for therapeutic use. Using a temporary complexation in the form of CORMs shows considerable promise, if we can learn to use these tools at the cellular level. A multidisciplinary team has been working toward this, and a therapeutic approach via CO may well enter the clinical sphere quite quickly.

Chapter 7, authored by Vanin, underlines the importance of dinitrosyl iron complexes with thiolate ligands in designing new therapies. Clinical trials of some of these species have begun in human subjects, and show a stable hypotensive effect without secondary effects on the human cardiovascular system. Chemists are working on stabilized forms of these species for wound repair. This is another innovative area of therapeutic research.

In addition to this therapeutics-oriented research, an awareness of the current high stakes in energy provides Chapters 8 and 9 with their focus on the progress of research on hydrogenases and their derivatives. These ancient enzymes possess an organometallic active site and are the subject of multifaceted research. The contribution of Bethel and Darensbourg focuses on the three hydrogenase families presently identified, their structure, their mechanism of action, the biosynthetic routes of their active site, and finally the most recent advances in the development of useful models of active sites. This work is a useful primer for Chapter 9 of Artero et al. that deals with the key technological aspects of the future.

Artero et al. offer a cutting-edge contribution on the economy of hydrogen and gives examples of constructions of new electrodes and photoelectrodes for hydrogen evolution and water oxidation, the two components of water splitting. Access to effective immobilized molecular catalysts is now becoming a possibility. Given the worldwide importance of energy issues, an international collaboration should rapidly lead to photoelectrocatalytic systems free from noble metals and viable economically. Such is the expectation raised by this study.

Hayashi et al. deal in Chapter 10 with artificial organometallic metalloenzymes, putting the accent on major trends and current challenges such as hybrid biocatalysts with abiotic activity or catalysis of cascade reactions. Notable challenges include the optimized adaptation of the organometallic cofactor within the active site, good targeting, hybrid robustness and recycling, and the introduction of abiotic activity into the cellular medium. These are avenues that are only waiting to be fully mapped out.

In Chapter 11, Licandro et al. have chosen to focus on a few innovative aspects within the thicket of organometallic bioprobes, specifically applications in cellular imaging. These studies are founded on the unique spectroscopic properties of organometallics allied with advances in instrumentation. Examples would be the combination of AFM and IR spectroscopy using metal-carbonyl probes, or new fluorescence microscopy techniques that open the way to high-resolution imaging of tissue. This field is multidisciplinary by its very nature, but metals such as Re, Ir, and Pt have produced the most promising fluorescent organometallic probes to date. This leaves room for other synthetic approaches to provide access to other bioprobes with different specific properties.

These few examples of the present state of the field show that bioorganometallic chemistry is connected to questions at the cutting edge of current research. Exploration of new avenues makes it possible to envisage innovative solutions to pressing social needs. The medicinal organometallic aspect is already very advanced, with the promise of novel treatments for incurable or difficult-to-treat diseases. The mechanistic approach is providing insight into the reasons for this breakthrough into previously unexplored territory. This volume will open up new research paths in this area, where a number of start-up companies have already begun.

The metalloenzymes and modeling area is still very open, and it is now clear that certain complexes will play a role in the energy transition that is currently underway. In addition, organometallic bioprobes, connected or not with theragnosis, represent a vast area needing only to be developed. The lines of force, the promises, and directions of travel in the field are...