The First Organometallic Selective Estrogen Receptor Modulators ...

Current Medicinal Chemistry, 2004, 11, 2505-2517

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The First Organometallic Selective Estrogen Receptor Modulators (SERMs) and Their Relevance to Breast Cancer Gérard Jaouena*, Siden Topa, Anne Vessièresa, G. Leclercqb and Michael J. McGlincheyc aLaboratoire

de Chimie Organométallique, UMR 7576, Ecole Nationale Supérieure de Chimie de Paris, 11, rue Pierre et Marie Curie, 75231 Paris Cedex 05, France

bLaboratoire

de Cancérologie Mammaire, Institut Jules Bordet, Rue Héger Bordet 1, Brussels 1000, Belgium

cDepartment

of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland

Abstract: 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 Cp2TiCl 2 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.

Keywords: Bioorganometallic Chemistry, ferrocene, metallocene, breast cancer, tamoxifen, SERM. PREAMBLE Breast cancer remains the predominant form of this disease with an incidence of about one in eight among Western women [1]. Cancer diagnosis and therapy are in constant evolution, in particular, because of our improving knowledge of the estrogen receptors structures (ERs) [2]. Indeed, there is an increasing understanding of the molecular function not only of estradiol, 1, the archetypical estrogen, but also of the anti-estrogenic Selective Estrogen Receptor Modulators (SERMs). The best developed of these (see Chart 1) are tamoxifen, 2, which is widely used to treat breast cancer, and raloxifen, 3, which is prescribed for osteoporosis, the most widespread ailment in the world and of considerable importance in determining our life spans. Despite the interest in these molecules [3], the number and complexity of the biological phenomena that come into play render non-viable the concept of an ideal and universal SERM. Nevertheless, one can study the function of the tissues, and select appropriate targets to aim for. In the overall scheme of the future development of new drugs for

*Address correspondence to this author at the Laboratoire de Chimie Organométallique, Ecole Nationale Supérieure de Chimie de Paris, 11, rue Pierre et Marie Curie, 75231 Paris Cedex 05, France; Tel: 33-1 43 26 95 55; FaxP: 33-1 43 26 00 61; E-mail: [email protected] 0929-8673/04 $45.00+.00

the treatment of breast cancer (unfortunately, tamoxifen is not effective against 40% of these types of tumours), it seems reasonable to study those molecules that are currently the most effective against ER-positive tumours, and even those that are ER-negative, with the aim of diminishing undesirable side effects, and the phenomenon of resistance [4-6]. In this context, the approach of using an organometallic SERM has not yet been explored. 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. We here describe the results of some of our investigations in this area. BRIEF DESCRIPTION OF THE MODE OF ACTION OF SERMS Our understanding of the mode of action of SERMs has benefitted from several important breakthroughs, of which we here highlight three of the most significant. Establishment of the Existence of two Estrogen α and ERβ β Determination of Their Receptors: ERα Structure and of Their Functional Domains For a long time, there was thought to be only a single estrogen receptor (now called the α receptor), its © 2004 Bentham Science Publishers Ltd.

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Fig. (1). Schematic representation of the primary structure of hERα and its functional domains (NHD : N-terminal domain ; NBD : DNA binding domain; LBD : ligand binding domain).

corresponding gene is found on human chromosome 6, and is widespread in a number of tissues, notably the uterus, and is often implicated in the phenomenon of reproduction. It is a 66 KDa protein, a member of the superfamily of nuclear receptors, possesses 595 amino acids, and is made up of six functional domains, as shown in (Fig. 1). Two key regions are the DNA-binding domain (DBD) and the ligand-binding domain (LBD). The primary function of ER is to activate

phosphorylated on at least five sites. A complex chain of events unfolds with a series of co-regulators depending on the tissue [7-12]. The discovery of the β estrogen receptor, located on human chromosome 14 came as a major surprise [13-16]. However, it is found in numerous sites such as the central nervous system, the cardiovascular system, the immune system, the urogenital organs, the kidneys, the lungs among

Fig. (2). Schematic representation of the primary structure of hERβ and its functional domains. The numbers into brackets represent the degree of homology (%) between respective domains in the two receptors.

gene transcription through binding of an estrogenic ligand to the receptor. This protein contains at least two transcription activation factors, AF1 and AF2. The second one requires association with a ligand to be activated. When ER is not bonded to the ligand it forms an inactive complex with Hsp 90, Hsp 56 (where Hsp = heat shock protein) and other chaperone proteins. Upon association of the estrogen with ER, Hsp 90 dissociates from the complex and ER is

Fig. (3). Schematic representation of the agonist binding site to ERα.

others. Moreover, as with the α receptor, it is also found in the mammary gland. Depending on the particular organ, these two receptors can, or cannot, act in a synergic fashion. It is interesting to note that these two receptors exhibit a high degree of homology in the DNA-binding domain, but only 59% homology in the ligand-binding domain (LBD) (Fig. 2 ). This discovery imparts a greater degree of complexity in terms of understanding the regulation

SERMs and Their Relevance to Breast Cancer

Current Medicinal Chemistry, 2004, Vol. 11, No. 18

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Fig. (4). Schematic representation of the antagonist binding site to ERα.

phenomena in the organism, but also offers new challenges to the chemist. In effect, one must now synthesise SERMs specifically functionalised so as to target a particular type of receptor. X-Ray Crystal Structural Determination of the Sites of Association of the Estrogens and Anti-estrogens with Their Receptors A recent series of articles has established the sites of association of estrogens and anti-estrogens with their receptors [17-20], and these are illustrated schematically in (Figs 3 and 4). Estradiol exhibits a mode of association

typical of an agonist: the phenol at position 3 is bonded to Glu 353, Arg 394 and a molecule of water, and the alcohol at position 17 is associated with His 524. Throughout the molecule there are a variety of lipophilic interactions with hydrophobic residues. A remarkable point of this attachment is a tweezer-type arrangement, which can only accommodate the phenolic A ring. As far as the remainder of the molecule is concerned, it can accept different hydrophobic groups, in particular, at positions 11 and 17 where the protein is more flexible [21-23]. (Fig. 4) illustrates the binding mode of an antagonist, in this case raloxifen, which exhibits similarities to the previous case, but also shows differences. The anti-estrogen

Fig. (5). Schematic representation of the interaction of OH-TAM with the Ligand Binding Domain in ERα.


Jaouen et al.

CH2-(CH2) 4-SO2- (CH2) 3-CF2-CF3

OH

O OH

CH2-(CH2)4-SO-(CH2)3-CF 2-CF3

HO ICI 182780

HO RU 58668 HO

ClCH2CH2

Toremifene

CH3CH2

OCH2CH2NMe2

Droloxifene

OCH2CH2NMe2

Chart 2.

is hydrogen-bonded by the OH groups in a similar fashion to that of estradiol (Glu 353, H2O, Arg 394 and His 524).

The opening of this pocket is characteristic of antiestrogenic behaviour towards the α receptor. One also sees

Fig. (6). Model of ER action at a classical ERE (Estrogen Response Element). The filled circles represent the ligand bound to the ER. reproduced from ref 25.

However, to accommodate the long basic chain (11Å) another pocket with a direct stabilising interaction through a hydrogen bond between the piperazine ring nitrogen and Asp 351 has been engendered in a flexible part of the protein. This ligand imposes a distinct conformation within the "Ligand Binding Domain", such that a specific helix (called helix 12, and which runs from residues 536 to 544) is now displaced relative to its activation position to the point of becoming an autoinhibitor.

these same general characteristics with hydroxytamoxifen, as shown in (Fig. 5). Here again, helix 12 occupies a part of the association groove of the co-activator. In fact, these studies allow us to account for, at the molecular level, the anti-estrogenic character of the entire series of phenolic molecules bearing basic or polar chains (Chart 2).

Fig. (7). Model of ER action at an ER-dependent AP1 (Activator Protein). The filled circle represents the ligand bound to the ER. reproduced from ref 25.



Identification of Two Different Activation Pathways According to the Site of Interaction (ERE or AP1) with DNA With the realisation that there are two sub-types of receptor, ERα and ERβ, two models for their activation have been discussed in the recent literature [24-28]. According to the originally accepted route, shown schematically in (Fig. 6), the receptor (α or β) becomes associated with the bioligand, and this complex dimerises. It is in this dimeric form that the complex becomes attached to a section of DNA at the "estrogen response element" (ERE) so as to initiate transcription (in the case of an estrogen), or not (in the case of an anti-estrogen). In this case, ERα and ERβ play a similar role. For example, tamoxifen in breast tumours blocks transcription mediated at the ERE either by ERα or ERβ. Another pathway has been recently identified that proceeds via the site entitled AP1 (activator protein 1), whereby the ligand is bonded to a monomeric receptor. This monomer binds to two proteins, Jun and Fos (J and F), and it is this complex which binds to the AP1 site of DNA and initiates transcription, as illustrated in (Fig. 7). It is crucial to understand that here in breast tissues, the receptors ERα and ERβ behave differently. Estrogens attached to ERα, and also anti-estrogens, although to a lesser extent, can stimulate transcription mediated by AP1. In contrast, transcription is inhibited by an estrogen (estradiol) complex attached to ERβ. Knowing that ERβ plays a role in the proliferation of tumours that are not amenable to treatment by tamoxifen [29], one can see that the agonist character of tamoxifen with ERβ via AP1 is an element to take account of in the search for new SERMs. At this point, it is interesting to note that E R β is also suspected to be implicated in the genecontrolled regulation of redox processes in the cell, notably the concentration of free radicals and reactive oxygen species [4].

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This degree of complexity is a serious challenge for the chemist searching for new molecules since it requires that one manipulate several parameters. The plot could thicken even more when one considers that the heterodimers ERα: ERβ have been identified [29]. The role of the activators present in target tissues should also be taken into consideration to explain the physiological effects [30]. STUDIES ON ORGANOMETALLIC SERMS: THE CURRENT SITUATION The status of inorganic complexes of platinum as effective anti-tumoural agents, the archetypical molecule being cisplatin, 4 [31-34], is very well known, even though the therapeutic spectrum is relatively narrow (testicles, ovaries and urogenital system and even colon). Among the most spectacular successes obtained with these compounds, we can cite the case of testicular cancer, which until recently, led irrevocably to the death of the patient, but which has now become an entirely curable illness. This advance initiated an avalanche of research on organometallic compounds of a wide variety of metals with the aim of finding new anti-tumoral agents [35]. Among these, the cyclopentadienyl complexes of Ti, Fe, Mo, V, Re and Ru have given encouraging results, even though no compound of this type has yet cleared the clinical stage [36]. Moreover, it appears as though the metallocenes operate according to mechanisms different from that of cisplatin, 4, and could perhaps be used on tumours for which 4 is ineffective. The idea of transporting cisplatin directly to the estrogen receptor by using a hormone (either an agonist or an antagonist) as the vehicle has been the object of several studies [37]. In this vein, we have synthesised the complex 5, based on a modification of the known drug oxaliplatin, 6,

CH3 CH2

OH H3N

Cl Pt Cl

H3N 4 cis-platin

Ti

CH3CH2

Cl Cl

O(CH2) 3NMe2 7

OH

CH3CH2 O O(CH2)3 NMe 2 O H2N

O Pt O NH2

NH2

O

CO

O

CO

OH

5

Fe O(CH2) nNM e2 CH3CH2

8[n] ; n = 2,3,4,5,8

Pt NH2 6

Oxaliplatin

Chart 3. molecules 4 - 6.

Re(CO) 3

9

O(CH2 )4NMe 2

Chart 4. Molecules 7 - 9.


Jaouen et al.

CH3CH2

CH3CH2 O

TiCl4 , Zn

O

(Z+E)

THF

yield = 54% Mn(CO) 3

O(CH2) 3NMe2

M n(CO) 3

O(CH2 )3NMe 2

10 hν, O2 Et2 O, MeOH 30 min

CH3CH2

1) nBuLi, THF -70°C to 0° C

CH3CH2 (Z+E)

2) CpTiCl 3 3) HCl gas Ti

Cl

Cl

O(CH2) 3NMe 2

O(CH2 )3NMe 2,HCl yield = 67%

7

11

yield = 98%

(Z+E)

Scheme 1. Use of the CpMn(CO)3 moiety for the synthesis of CpCp'TiCl2 complexes.

in which 1,2-diaminocyclohexyl and oxalate ligands are bonded to platinum. In 5, it was necessary to replace the oxalato ligand by malonato to provide a site of attachment to the tamoxifen skeleton; however, the results on mammary tumours have been disappointing [38]. We must therefore be more flexible in our strategy, and explore the potential of a wide variety of possible cytotoxic organometallics attached to SERMs so as to optimise these effects. The current relevance of this topic has been enhanced by recent progress, both mechanistic and structural, in the area of receptors has placed this research on a molecular basis. In this context, we have expanded this area by investigating not only the platinum complex but also other series of organometallic SERMs. The complexes of Ti (7), Fe (8), Re (9) are depicted in Chart 4. Dichlorotitanocene, Cp 2 TiCl 2 , has shown activity against Erhlich's ascite tumour, as have certain ferrocene derivatives in their oxidised form as ferricinium ions, while C p R e ( C O ) 3 could turn out to be an ideal model for radiopharmaceuticals containing 188Re or 99mTc [39]. FIRST TAMOXIFEN MODIFIED BY ATTACHMENT OF A TITANIUM METALLOCENE. EVIDENCE FOR AN UNEXPECTED BIOLOGICAL BEHAVIOUR The work of Köpf-Maier carried out with (Cp)2 TiCl 2 indicates that this unsaturated electrophilic Ti(IV) metallocene possesses cytoxic properties against various

types of tumours both in vitro and in vivo [36]. It was thus tempting to envisage the synthesis of molecules such as 7 in order to evaluate their anti-proliferative effects on breast cancer cell lines in the hope of accessing a more efficacious SERM than tamoxifen. However, one must consider that the preparation of 7 raises real synthetic problems because of the rather poor stability of titanium metallocenes in solution, thus posing a challenging target for the chemist. The difficulty of handling a metallocene of the type (Cp')TiCl2(Cp) throughout a multi-step procedure led us to envisage a strategy whereby the moiety "CpTiCl2" would be introduced only in the last step of the synthetic sequence. After numerous failed attempts, we were obliged to devise an innovative synthetic route to the desired molecule [40]. The key step of the synthesis is illustrated in (Scheme 1), and relies on ready access to the cymantrenyl tamoxifen, 10, via a McMurry cross-coupling reaction. This latter complex can be photochemically oxidised in a protic solvent and allows the recovery of the diene 11 in 98% yield. The presence of the protic solvent, which leads to the trapping of the short-lived dienyl intermediate as a diene, is crucial for the success of the reaction [41]. The transformation of the diene, 11, into the desired cyclopentadienyl-titanium complex, 7, is carried out classically, in 67% yield, by treatment with n-BuLi and CpTiCl3 successively. The final product is treated with HCl to enhance both its stability and solubility in water. The putative anti-estrogenic activity of 7 has been studied on MCF-7 cells, hormono dependent breast cancer


cell which is the archetypical model for tumours classified as ER(+) [42]. We determined the proliferative/anti-proliferative effect directly on the cultured cell samples by comparing the number of cells in metal complex-treated and untreated samples after incubation. Assuming that the quantity of DNA is proportional to the number of cells, we used DNA as a convenient marker to assess the extent of proliferation.

Fig. (8). Estrogenic activity of 7 on MCF7 cells (hormono dependent cancer cell line). The results are expressed as the percentage of DNA in the sample versus the DNA value of the control after five days of culture. The number in brackets corresponds to the Log value of the molarity of incubation.


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(Fig. 8) shows the expected estrogenic activity of estradiol at 10 -10 M and anti-estrogenic activity of hydroxytamoxifen, at 1x10-7 M. The results obtained with the Ti complex 7 over a range of concentrations (1x10-6 to 1x10 -8 M) are also collected in this Figure. They are surprising: contrary to what had been anticipated, they show clearly that complex 7 acts as an effective estrogen, and not as an anti-estrogen, despite the presence of the alkyldimethylamino chain that is considered to be responsible for the anti-estrogenic effect of tamoxifen. A moment's consideration leads one to suspect that the estrogenic effect derives from the presence of the organometallic moiety. Therefore, the same test was carried out on dichlorotitanocene itself, Cp2 TiCl 2 , and the results are presented in (Fig. 9). They show clearly that the organotitanium compound behaves as a powerful estrogen with effects comparable to those of estradiol. The unexpected behaviour of dichlorotitanocene remains to be explained. Since the biological solvent par excellence is water, we note that the hydrolysis of Cp2TiCl2 has been extensively studied [43, 44]. Many reactions can occur, some are shown in (Scheme 2). First of all, the protonolysis of the cyclopentadienyl ligand has been shown to yield a cyclopentadiene and a metal hydroxide, however, these are minor products. Another reaction pathway involves hydrolysis of the chloride leading to myriad mono- and bimetallic complexes; among these we consider, for example, Cp 2 Ti(OH)Cl. There is evidently an aromatic ring and a neighbouring hydroxyl group. Can one visualise that this, or another of the hydrolysis products, could mimic the phenol of the A ring of estradiol and initiate an estrogenic effect? We have already seen the importance of this phenolic character in the model of the structure of the alpha estrogen receptor, as depicted in (Fig. 3). 1) Cyclopentadienyl protonolysis :

H 2O

hν

OH M

Mn(CO)3 2) Chloride hydrolysis : Cp2Ti(H2O)Cl+ Cp2Ti(H2O) x(OH)(2-y)+ Cp2Ti(H2O) 22+, Cp2Ti(OH)Cl etc., dimers.

Scheme 2. Some hydrolysis chemistry of cyclopentadienyl metal complexes.

Fig. (9). Estrogenic activity of Cp2TiCl2 on MCF7 cells (hormono dependent cancer cell line). The results are expressed as the percentage of DNA in the sample versus the DNA value of the control after 5 days of culture. The number in brackets corresponds to the Log value of the molarity of incubation.

However, a recent study by Sadler has shed new light on the behaviour of Cp2 TiCl 2 in biological media [31]. According to this work, the most rapid hydrolysis occurs at the level of the chlorides. The role of the cyclopentadienes is to slow a too-rapid hydrolysis, which would lead to inactive polymers, but the Cp entities are subsequently displaced during the process. Whether or not this is the case, the result is a monomer of TiIV, a hard metal similar to FeIII, which is quickly captured and stabilised by transferrine, one of the iron-carrying proteins in the blood. It has been shown that the level of transferrine receptor is greater at the surface of cancerous cells, perhaps due to their increased demand for


Jaouen et al.

iron. Because of the change in pH at this level the TiIV is then released and is transported to the centre of the cell by binding to ATP. It is clear from the above that depending on the specific nature of the target cells, differentiated behaviour may be expected. And in fact, although titanium has not yet been studied in this context, the role of certain metal ions has already been the subject of occasional analyses in relation to estrogen receptors. For example, treatment of the receptor with Cd2+ in very low concentration (1 nM) results in coordination of this metal at the level of the ligand binding domain [45]. The complex formed with this exogeneous metal activates ER alpha just as binding to estradiol would. Actually, Cadmium is able to coordinate with cysteins 381 and 447, glutamic acid 523, histidine 524 and aspartic acid 538 of the receptor ligand binding domain. In so doing it competes with estradiol and inhibits its binding to the ER. The idea is that this type of coordination may cause the receptor to act in the same way as the natural ligand does, by snapping the trap shut between the two helices H4 and H12 that causes the activation of the transcriptional machinery and proliferation of hormono dependent breast cancer cell line (MCF7 cells). This hypothesis is an appealing one that will be confirmed or denied by further studies. It also remains to be seen whether the explanation advanced for Cd2+ holds good for Ti4+ . Interestingly, a molecular modelling study shows that cystein 381, glutamic acid 380 and histidine 547, are well positioned to coordinate Ti IV (Fig. 10). (Cabestaing unpublished results). Whatever is the intimate nature of this phenomenon, it remains the case that the initial objective has not been achieved, and that it would appear to be difficult to use titanium metallocenes in the battle against breast cancer. However, the novel synthetic route developed may be useful for other purposes.

TAMOXIFENS MODIFIED BY FERROCENES: THE FERROCIFENS. SYNTHETIC ACCESS AND ANTIPROLIFERATIVE EFFECTS ON BOTH HORMONO DEPENDENT (MCF7) AND INDEPENDENT (MDAMB231 CELL LINES) For some time we have sought to replace the β phenyl ring in tamoxifen by an aromatic ferrocenyl substituent. The cytotoxic properties of the ferricinium cation (Fc+•), which is easily formed in biological media by oxidation, are well known. One might therefore hope that, by this approach, one could obtain an estrogenic vector endowed with enhanced cytotoxic properties [46,47]. The synthetic objective was achieved by using the McMurry coupling reaction, and complex 8, which possesses a basic –O-(CH2 ) n N(CH 3 ) 2 chain, in this case containing three methylene groups, is shown in (Scheme 3 [48]. The global yield of isolated product is 29%. In fact, molecule 8[3] (n = 3), is formed in a 50/50 Z/E ratio of the two diastereomers, which are separable by chromatography, although with difficulty. However, simple redissolution of either pure Z, or pure E, in a protic solvent (alcohol, water) regenerates the initial mixture. This occurs because of the great stability of carbenium ions adjacent to an organometallic system (pKR+ = -1 for FeCH2+). In practice, for biological experiments, it suffices to use the Z/E mixture since these forms rapidly equilibrate in aqueous media. This question of isomerisation bears similarities to the case of tamoxifen (or hydroxytamoxifen, though the former is administered, it is the OH-TAM that is active) even though its pKR + is lower and the stabilisation less pronounced (pKR+ Fe3+ + O2-•

Jaouen et al. [19] [20] [21]

Fe2+ + O2-• + 2H+ ----------> Fe3+ + H2O2. Fe2+ + H2O2 ----------> Fe3+ + OH- + OH•. The superoxide radical, O2-•, shows very little reactivity towards DNA, whereas the OH• radical is very reactive, provoking diverse types of lesions, and is considered to be very genotoxic. The behaviour of the rhenium complex, 9 which is relatively resistant towards oxidation, fits in with this tentative explanation. This hypothesis, which clearly still requires more support and verification, is in accord with other recent articles [63,64]. However, other possibilities certainly cannot be discounted at this time. It is interesting as more than just an example; it takes account of the unique character of the ferrocifens, which are capable of behaving as antiproliferative species with each of the two estrogen receptors by bringing into play two different mechanisms. It opens a new window on organometallic oncology, validates and encourages the research of other manifestations of the phenomenon in other biological systems, and offers fascinating perspectives for the emerging domain of bioorganometallic chemistry [65-67]. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

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