There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Eating five servings of fruits and vegetables per day! This is what is highly recommended and heavily advertised nowadays to the general public to stay fit and healthy! Drinking green tea on a regular basis, eating chocolate from time to time, as well as savoring a couple of glasses of red wine per day have been claimed to increase life expectancy even further! Why? The answer is in fact still under scientific scrutiny, but a particular class of compounds naturally occurring in fruits and vegetables is considered to be crucial for the expression of such human health benefits: the polyphenols! What are these plant products really? What are their physicochemical properties? How do they express their biological activity? Are they really valuable for disease prevention? Can they be used to develop new pharmaceutical drugs? What recent progress has been made toward their preparation by organic synthesis? This Review gives answers from a chemical perspective, summarizes the state of the art, and highlights the most significant advances in the field of polyphenol research.

Plant Polyphenols: Chemical Properties, Biological Activities, and Synthesis

The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects.

In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics).



Figure 1

Summary of the typical classes of organometallic compounds used in medicinal chemistry.



In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

http://pubs.acs.org/doi/pdf/10.1021/jm100020w

Organometallic Anticancer Compounds

Bioorganometallic Chemistry of Ferrocene

New trends for metal complexes with anticancer activity.

Despite current developments in therapeutics focusing on biotechnologically-oriented species, the unflagging utility of small molecules or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small molecules, while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chemistry. Medicinal organometallic chemistry can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clinical development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable aromatic, with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concentration of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.

/pdf/ferrocifen-type-anti-cancer-drugs-5dz1akizk5.pdf

Ferrocifen type anti cancer drugs.

Ferrocene‐Mediated Proton‐Coupled Electron Transfer in a Series of Ferrocifen‐Type Breast‐Cancer Drug Candidates

A series of ferrocene derivatives based upon the structure of the antiestrogenic drug tamoxifen or of its active metabolite hydroxytamoxifen has been prepared and named by analogy ferrocifens and hydroxyferrocifens. This series includes 1-[4-(O(CH(2))(n)NMe(2))phenyl]-1-phenyl-2-ferrocenyl-but-1-ene and 1-[4-(-O(CH(2))(n)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene, with n=2, 3, 5 and 8, and 1-[4-(-O(CH(2))(2)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenylethene. Most of these molecules have been synthesised by McMurry cross-coupling of the appropriate ketones, except for the ethene complexes, which were prepared by a four-step reaction sequence starting from the ferrocenylacetic acid. All these compounds were obtained as mixtures of Z and E isomers. The isomers were separated in the cases of the ferrocenyl derivatives of tamoxifen and hydroxytamoxifen (n=2). No isomerisation of the Z and E isomers occurred in DMSO after one day, while a 50:50 mixture of the isomers was obtained within one hour in chloroform. The X-ray structure of (E)-1-[4-(-O(CH(2))(2)NMe(2))phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene has been determined. The relative binding affinity (RBA) values of the hydroxyferrocifens for the estrogen receptor alpha (ERalpha) was good to moderate, with values decreasing progressively with the length of the basic chain. The RBA values found for the estrogen receptor beta (ERbeta) are equal to or slightly less than those found for the alpha form. The lipophilicity of the hydroxyferrocifens are superior to the values found for estradiol and increase with lengthening of the chain. The antiproliferative effects of the four hydroxyferrocifens with n=2, 3, 5 and 8 were studied on four breast cancer cell lines (MCF7, MDA-MB231, RTx6 and TD5) possessing different levels of ERalpha. On MCF7 cells containing high levels of ERalpha, hydroxyferrocifens behave as antiestrogens. At a molarity of 1 microM the effect is close to that of hydroxytamoxifen (used for reference) when n=2 or 5, more marked when n=3, and weaker when n=8. Ferrocene alone has no effect. For the MDA-MB231 cells, classed as a hormone-independent breast cancer cell line, on the other hand, the hydroxyferrocifens show remarkable antiproliferative behaviour while the hydroxytamoxifen is completely inactive. Hydroxyferrocifens therefore show the unique property of being active both on hormone-dependent and on hormone-independent breast cancer cell lines. The molecular modelling study provides some clues for understanding of the antagonist effect of these molecules, while an additional cytotoxic effect due to the vectorised ferrocenyl unit is revealed in some occasions.

Synthesis, biochemical properties and molecular modelling studies of organometallic specific estrogen receptor modulators (SERMs), the ferrocifens and hydroxyferrocifens: evidence for an antiproliferative effect of hydroxyferrocifens on both hormone-dependent and hormone-independent breast cancer cell lines.

Bioorganometallic chemistry: a future direction for transition metal organometallic chemistry?

In the overall scheme of the future development of new drugs for the treatment of breast cancer, specially tamoxifen resistant tumours, we have explored the unprecedented use of organometallic SERMs. The initial idea is to enhance the efficacy of the current standard, i.e. tamoxifen, by modifying the structure through judicious incorporation of an organometallic moiety possessing novel properties. Results have been varied, justifying a systematic approach that has proved to be full of surprised. The following differing situations were observed (a) the anti-proliferative effect is due to the vector and the organometallic moiety does not improve the effects of the SERM, no matter what concentration is used. In particular, this is the case for the hydroxytamoxifen derivative bearing a CpRe(CO)3 group, which behaves almost identically to hydroxytamoxifen. These stable species have future promise for use with radionucleides of Re and Tc (b) the effect of the organometallic moiety counteracts the anti-estrogenic behaviour of the vector and leads to species with proliferative activity; this is the case with Cp2TiCl2 entity, which when attached to tamoxifen behaves as a powerful estrogen, probably due to in situ release of Ti(IV) (c) a synergy exists between the cytotoxic organometallic moiety and its organic vector, leading to unique anti-proliferative effects on breast cancer cells classed ER+ and ER-. This result opens a new window on organometallic oncology. It is also clear that the range of possibilities is broad, varied and currently unpredictable. A systematic study combining organometallic chemistry and biology is the only option in the search for new SERMs with novel properties.

Anne Vessières

Papers

Ferrocifen type anti cancer drugs.

Ferrocene‐Mediated Proton‐Coupled Electron Transfer in a Series of Ferrocifen‐Type Breast‐Cancer Drug Candidates

Bioorganometallic chemistry: a future direction for transition metal organometallic chemistry?

The first organometallic selective estrogen receptor modulators (SERMs) and their relevance to breast cancer