Ferrocifen type anti cancer drugs.

TLDR: It is shown 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.

Abstract: 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.

Figures

Table 3 IC50 values of a selection of complexes in the ferrocenyl acyclic and ansa series

Table 4 : IC50 values (µM) of organic and ferrocenyl hybrids of SAHA and PSA on MDAMB-231 cancer cells after 72h. 47

Figure 1 : Image of Fc-OH-Tam (n=4) docked in the ligand binding domain (LBD) of ERα with an antagonist conformation. (Adapted from the LBD X-ray structure)54

Table 1 : Lipophilicity and Relative binding affinity (RBA) values for the estrogen receptor (α and β forms) of some ferrocifens 29,30

Figure 2 : ROS production in MDA-MB-231 (1 µM, 10 min, H2DCFDA as fluorescent probe, mean of two experiments)

Table 2 Antiproliferative effect of OH-Tam and Fc-OH-Tam with n = 3 or 4 on various cell lines and comparison with their ERα and ERβ content.

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Ferrocifen type anti cancer drugs
Gérard Jaouen, Anne Vessières, Siden Top
To cite this version:
Gérard Jaouen, Anne Vessières, Siden Top. Ferrocifen type anti cancer drugs. Chemical Society
Reviews, Royal Society of Chemistry, 2015, 44 (24), pp.8802-8817. �10.1039/C5CS00486A�. �hal-
01221048�

1
Ferrocifen Type Anti Cancer Drugs
Gérard Jaouen,
a,b,c
* Anne Vessières,
a,b
Siden Top
a,b
a
Sorbonne Universités, UPMC Univ Paris 06, IPCM, F-75005 Paris, France
b
CNRS, UMR 8232, IPCM, F-75005 Paris, France
c
PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, F-75005 Paris,
France
Corresponding author :
Prof G. Jaouen, Chimie ParisTech, 11 rue Pierre et Marie Curie, F-75005 Paris, France.
Tel : 33 (0)1 43 26 95 55
Email : gerard.jaouen@chimie-paristech.fr
to the memory of Professor Lord (Jack) Lewis, an inspiring mentor

2
Biography
Professor Gérard Jaouen received his doctorate from the University of Rennes (France) in 1973, and
spent the year 1973-1974 at Cambridge working with Professor Lord (Jack) Lewis. He became
Professor at the University of Paris 6 (ENSCP) in 1982, where he set up a CNRS Associated
Laboratory and decided to focus on bioorganometallic chemistry. This initially embryonic field has
now flourished. He is the editor of 3 books, the author of 425 papers, including 18 chapters and
reviews, and has filed 16 patents. His achievements in the field have been recognized by several
international awards. He was awarded Knight of the “Légion d’Honneur” (2006), and was elected as a
fellow of the European Academy of Sciences and a member of the Academia Europaea (2012)
Anne Vessières, a Director of Research in the CNRS, earned doctorates in both organometallic
chemistry (1974) and biochemistry (1980) from the University of Rennes (France). She spent several
periods as a visiting scientist at McGill University, Montreal, with Professor Ian S. Butler, and at the
Jules Bordet Hospital, Brussels, with Professor Guy Leclercq. In 1982 she helped to set up the
Organometallic Chemistry Laboratory at the ENSCP. Her two main fields of interest are Medicinal
Chemistry and the use of metal carbonyl complexes for mid-infrared detection. In 2012 she was
awarded the Elsevier Award for Outstanding Achievements in Bioorganometallic Chemistry
Siden Top, born in Cambodia, is a Director of Research in the CNRS. In 1972 he was awarded a
fellowship to study in France where he obtained a “Docteur Ingénieur” degree in Dijon (1976) and a
PhD in 1979 in Rennes, working with Professors R. Dabard and G. Jaouen. In 1982, he moved to the
ENSCP and has worked mainly on bioorganometallics. He spent the year 1987 with Professor H. D.
Kaesz at UCLA, and several short periods with Professor M. J. McGlinchey at McMaster University.
His research focuses on the development of organometallic compounds as anticancer agents and
radiopharmaceuticals.

3
Abstract: 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.
1 Introduction, Contextualizing the Problem
We are now witnessing an explosion of cases of cancer, a disease whose multiform
nature makes it very difficult to treat. We have reached the stage where we may be said to
have entered “the Age of Cancer”
1
with 6.5 million cancer deaths in 2003, reaching 12
million in 2013, and predictions for 2030 of 22 million deaths, 35 million by 2050. It is vital
to give the lie to these dark predictions. The numbers reflect an increase that is statistically
greater than the increase in population of the planet.
In parallel with this explosion of the disease, major innovations in the therapeutic
approach to cancers, complementing established methods such as surgery and ionizing
radiation, have appeared in the last decade. Progress has been made for example in improved
targeting of cancerous sites, whether by the use of biodegradable nanoparticles, dendrimers,

4
monoclonal antibodies, peptides or saccharides bound to appropriate ligands or indeed the use
of microfluidics.
2, 3
All this contributes to the progress of chemotherapy and hormone therapy.
But the improvements are also driven by a flood of biological information supporting the
understanding of cancers and permitting greater personalization of treatment. Chemistry still
often plays a central role, however, in bringing these new approaches to fruition.
It must nevertheless be borne in mind that the cost of these new highly targeted
treatments is a pressing problem, placing a heavy burden on the health budgets of the majority
of developed and developing countries. Herceptin, Mabthera, Avastin, flagship products of
Roche, earned 21 billion dollars in 2013.
1
Within the current progression, Kadcyla looks
poised to enter the same territory. These drugs exemplify the biopharmaceutical approach
(selective monoclonal antibodies for well-targeted cancers, but at exorbitant public cost).
If we hope to find new active principles while holding down costs, we need to look in the
direction of innovative chemotherapies, ideally outside the well-worn paths of traditional
chemistry. Interestingly, these days, the traditional disciplines of chemistry appear to be
undergoing a profound and rapid evolution, for example in chemical biology, in their drive to
explore new directions beyond the well traveled pathways, and to build structures of
increasing complexity and diversity. Molecular chemistry is no exception to this fundamental
trend.
In particular, we are currently perceiving a scientific interest in a diversity of structures
produced by inorganic syntheses.
4
This approach has already broken through into the domain
of healthcare, whether in therapy, thanks for instance to the importance of Pt coordination
metallodrugs or in diagnostic imaging, with MRI contrast agents based on Gd, or indeed in
radiopharmaceuticals designed around the radionucleide
99m
Tc, to give only a few examples.
In this context the value of platinum coordination complexes in oncology is well known
with three of these complexes (vide infra) being used, alone or in combination, in 70% of
cancer treatments.
5
This is despite the well-documented disadvantages of these DNA
alkylating agents; their use is in fact sometimes only the result of a lack of alternatives. The
coordination complexes of Pt induce cell death primarily by apoptosis thus they are
ineffective in the treatment of tumor cells resistant to this pathway. This is often the case with
cancers that are difficult to treat and that have poor outcomes. Considering these gaps in the
therapeutic arsenal a coordination chemistry of Ru has been explored and some promising
molecules such as NAMI-A or KP1019 have been obtained (Chart 1).
6

Frequently asked questions

Q1. What have the authors stated for future works in "Ferrocifen type anti cancer drugs" ?

This series was conceived initially as ferrocenyl derivatives of tamoxifen — the primary prodrug to combat hormone-dependent breast cancers — in an attempt to extend the range of applicability to hormone-independent cancers. Moreover, as for Fc-OH-Tam, the two species induce senescence at low concentration ( 0. 1 µM ) and, depending on the cancer cell, a possibility of apoptosis at higher concentrations ( > 1 µM ) as a function of the sensitivity of the cell to pro-apoptotic stimuli. The possibility of activity at concentrations appropriate for Fenton reactions, which engender a genotoxic effect by producing hydroxyl radicals, is encouraging for the potential utility of their molecules. One can hope that this review may stimulate other, more biochemically focused groups, to extend these studies to include metabolomic or microarray expression profiling of appropriate cell lines to deconvolute the multiple pathways involved. 

Q2. What contributions have the authors mentioned in the paper "Ferrocifen type anti cancer drugs" ?

The Archive ouverte pluridisciplinaire HAL ( HAL ) this paper is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. 

Q3. What is the example of a diastereomer treating ex vivo primary?

A promising example of a diastereomer treating ex vivo primary lymphoblasts isolated from children is 14 which appears to make it possible to overcome resistance. 

Q4. what is the effect of fc-OH-Tam on thioredox?

The effect of Fc-OH-Tam and Fc-monoOH on Jurkat cells shows that the strongest inhibition of the thioredoxin reductase is induced after incubation in the presence of Fc-OH-Tam. 

Q5. What was the main reason for the delay in the arrival of organometallic frameworks?

7The arrival of organometallic frameworks constructed by design, with a precisebiological endpoint in mind, was somewhat delayed, owing to an emphasis on catalysis which for some years had the effect of relegating other aspects of the field to obscurity. 

Q6. What is the role of ferrocifens in cancer?

Since the authors know that P450 cyctochromes exist in cancerous cells, such a metabolite could play a role in the toxicity of the ferrocifens. 

Q7. What is the mechanism for the formation of quinone methides?

A redox process involving two electrons and two protons leading to formation of a phenoxy radical and then a quinone methide has been suggested as being the origin of the high toxicity of these molecules (Scheme 4). 

Q8. What is the effect of Fc-OH-Tam on melanoma cells?

At elevated concentrations (5 – 25 µM) the complex Fc-OH-Tam induces a rapid rounding of the cancerous cells (melanomas, MDA-MB-231, MCF-7) followed by their detachment. 

Q9. What is the effect of ferrocene on MCF-7 cells?

These tamoxifen-like complexes have an antiestrogenic antiproliferative effect on MCF-7 cells, identical to that of the ferrocifens where the mono and diphenolic complexes have an estrogenic effect. 

Q10. What is the main reason for the discovery of this senescence?

The discovery of this senescence is not without therapeutic interest since it could provide a promising alternative to cytotoxic compounds, in particular to avoid the problem of their chemoresistance. 

Q11. What is the effect of the ferrocifenyl entities on cancer cells?

these ferrocifenyl entities, which are frequently producers of ROS, are active essentially on cancerous cells and are much less so on healthy cells. 

Q12. What is the effect of a quinone methide on ferrocene?

In effect, this complex that lacks the phenolic group cannot lead to formation of a quinone methide that could play a decisive role in the toxicity of the most active complexes (see below) and leads to cell death by apoptosis and not to inactivation via senescence as with the other complexes. 

Q13. What did it become apparent that the ferrocifens targeted?

it quickly became apparent that the ferrocifens, unlike the platinum complexes, targeted primarily not the DNA bases but rather the proteins. 

Q14. What is the redox potential of ferrocenes?

This could be associated with the redox potential of the three metallocenes (0.47, 1.03, 0.83V, respectively for ferrocene, ruthenocene and osmocene), which results in an easier oxidation of ferrocifens than ruthenocifens and osmocifens. 

Q15. How many of these complexes are used in cancer?

In this context the value of platinum coordination complexes in oncology is well knownwith three of these complexes (vide infra) being used, alone or in combination, in 70% of cancer treatments. 

Q16. What is the ferrocifens's role in cytotoxic substances?

Chart 6 : Quinone methide radical derived from ansa-Fc-diOHIn all cases the quinone methides and their radical precursors are potentially veryreactive intermediates and one could regard the ferrocifens as pro-drugs that allow the generation of these cytotoxic entities in the right place.