The Ferrocifen Family as Potent and Selective Antitumor Compounds: Mechanisms of Action

Abstract

Chemical Biology, a discipline that links chemical engineering and biology, differs from biochemistry by positioning itself as a broad chemical domain that makes available to biology the tools and techniques of chemistry, and thus allows biological entities to be controlled, manipulated, redirected or even transformed [1–3]. It has proved over the past number of years to be a scientific goldmine for molecular chemistry. We became involved via the biological aspect of the transition metal organometallics, a domain we helped to create under the title of Bioorganometallic Chemistry, and which made its first appearance in 1985 [4–6]. This field of research encompasses organometallics in biology and medicine, and indeed could be seen as an organometallic component of chemical biology. At the beginning of the 1980s, the domain of organometallic catalysis held the high ground and its domination left little space for other fields of exploration. One important discovery, in the vitamin B12 series, the B12 coenzyme, methylcobalamine, was made by Dorothy Hodgkin whose determination of the structure of vitamin B12 by X-ray diffraction in 1956 earned her the Nobel Prize in 1964 [7]. However, this discovery of a proven role for organometallics in biology remained for some time an isolated example among the metalloenzymes of coordination complexes. The first structures of organometallic hydrogenases, for instance, date from 1995 [8, 9]. A few chemists however did take an interest in models of the vitamin B12 family as, in terms of their reactivity, their behavior was sometimes reminiscent of that of Grignard and Meerwein’s reagents, and they could be sources of radicals for 1,2 rearrangements (e.g., of glutamic acid). This provided a conceptual basis that was reasonably familiar thanks to the connection with complexes with σ -type M–C bonds. This line of research however remained marginal. In fact one of the core beliefs prevalent at that time was that organometallics were unstable in the presence of oxygen and unusable in aqueous media. This doctrine made any large-scale application in biology prohibitive. Subsequently, this conviction was shown to be misplaced for myriads of organometallic complexes, thanks to the work of a few pioneers [10]. These early breakthroughs gradually lifted the taboos, liberated earlier restricted thinking, and overturned a number of unfounded assumptions. The viability of organometallics in biology has been the norm now for some years [11] and has allowed a new research community to develop. It is clear now that the flexibility of these species, the breadth of their applications, and their novel functionality provide a powerful stimulus to innovate. Their distinctive properties are finding ever wider applications within this new conceptual framework [10–16]. Organometallic chemical biology may be seen as a subset [17] of Inorganic Chemical Biology [18, 19] recently defined as referring to metal complexes of all kinds, without specifying the type of ligand–metal bonds involved. An organometallic