Chemistry and catalysis advances in organometallic chemistry and catalysis
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42.2 CONTEXT AND BACKGROUND In the arsenal of anticancer metallodrugs, the coordination complexes of platinum are currently the most commonly used antineoplastic agents as, alone or in association, they are involved in more than 70% of treatments [45–47] The coordination complexes shown in Fig. 42.1 represent some of the most widely used species. Worldwide, hospitals that do not use these species can no longer be found [48] and their usefulness continues to grow.
in the treatment of head and neck tumors and those of the bladder [45]. Besides cis-platin, the less aggressive carboplatin 2 and oxaliplatin 3 were later introduced, the latter specifically for treatment of colorectal cancers. At the present time, a dozen other Pt complexes are in advanced clinical trials, and three derivatives (nedaplatin, loboplatin, and heptaplatin) are in clinical use although less universally so [48]. A key element in the mechanism of action of cis-platin 1 is the coordination of platinum to the N7 site of two adjacent guanines, causing a distortion of the DNA structure at the level of the cell nucleus and probably also that of the mitochondria [48]. It may perhaps be useful to mention here that, compared to the other group 10 metals (Ni, Pd), Pt shows higher activity linked to the kinetic exchange rate of this metal. Despite their usefulness, these Pt compounds have a number of drawbacks including a high level of toxicity, susceptibility to resistance, a tendency to cause renal problems, and a still limited effective range [45]. These shortcomings led to development of the antitumoral chemistry of Ti and Ru, in which the first results, obtained by Dwyer et al. [49, 50] and now largely forgotten, date from the 1950s, 10 years before Rosenberg’s serendipitous discovery of the properties of
Studies on the medicinal applications of Ru compounds [52–54] have been facilitated by the great diversity in the coordination and organometallic chemistry of Ru, both from a fundamental perspective [55] [56] as well as in relation to its use in catalysis [57] and photochemistry [58]. It is expected that this metal of the iron group may possess lower toxicity than H 3
Pt H 3 N Cl Cl H 3 N Pt H 3 N O O O O N H 2 Pt H 2 N O O O O cis-Platin 1 Carboplatin 2 Oxaliplatin 3 Second
generation Third
generation Substitution of chorides Substitution of amines
The most widely used coordination complexes of Pt. CONTEXT AND BACKGROUND 565 Pt. In addition, even though Ru(III) is the predominant oxidation state in physiological conditions, the oxidation states Ru(II) and Ru(IV) are easily accessible in the presence of either biological reducing agents (such as ascorbate or glutathione) or oxidizing agents (O 2 or H
2 O 2 ) [59–61]. The three oxidation states of Ru form octahedral coordination complexes (usually with ligands bearing relatively soft nitrogen- or sulphur-containing groups). In contrast, typical organometallic complexes of Ru(II) are tetrahedral (pseudo-octahedral piano-stool geometry), often with a π-bond to an arene ligand. The history of the development of the anticancer drugs of Ru has been abundantly reported [59] [62–68]. We note only a characteristic of the evolution of this research. The first anticancer compounds of Ru, suggested by Clarke in the 1980s, for example, complex 4, were clearly inspired by cis-platin [69] [70]. A gradual evolution has taken place toward complexes such as NAMI-A 5 reported by Sava and Alessio [55, 64, 65, 71] and KP1019 6 by Keppler [72–76] that are fairly stable in terms of aquation and hydrolysis, and which are already in phase I or II clinical trials. Promising organometallics [77] include Ru(II) arenes such as RAPTA 8 reported by Dyson [67, 78], complexes of type 7 by Sadler [66, 79], and compound 9 by Pfeffer [80, 81] (Fig. 42.2). These latter complexes 7, 8, and 9 belong to the organometallic family. With the exponential explosion of research into anticancer metallodrugs some original entities of Ru act via a structural role for the metal, which would give its shape to the compound and would favor noncovalent interactions with the target, as for example the organometallic 10 (Fig. 42.3), an excellent inhibitor of certain protein kinases developed by Meggers [27, 82]. The success of the anticancer drugs based on Pt and an understanding of their mechanism of action has weighed heavily on a large part of the research into other metallodrugs, and even on the search for other metal-based systems where, more or less implicitly, similarities with Pt have tended to be sought. In a sense, as underlined appositely by Keppler, Jakijec et al. [68], this presumption has tended to act as a brake on the development of new systems of anticancer metallodrugs. It is clear that several initiatives, thanks to some imaginative thinking, have succeeded in moving away from the initial classification scheme. These include antimetastatic entities such as NAMI-A or RAPTA [71, 78], which open up new approaches at the mechanistic level. The discovery of mechanisms of action beyond those that lead to apoptosis of cancer cells by alkylation of DNA by platinum is in fact an important challenge to address [78, 83, 84]. This may allow us to find new metallodrugs able to treat apoptosis-resistant cancers via alternative mechanisms (e.g., senescence). This can be envisioned for the ferrocifen derivatives [85]. Ru III
Cl Cl Cl Cl N S O CH 3 H 3 C NH N H NH Ru III
Cl Cl Cl Cl N N KP1019 HN NH N H HN Ru H 2 N Cl NH 2 R
6 7 Ru Cl Cl 8 P N N N N N N Ru N N
NAMI-A Ru
Cl Cl NH 3 NH 3 NH 3 NH 3 4 PF 6 − Cl − PF 6 − Figure 42.2 Some promising anticancer Ru complexes. N N
HO O O Ru CO
Figure 42.3 Example of an inhibitor of certain protein kinases. 566 THE FERROCIFEN FAMILY AS POTENT AND SELECTIVE ANTITUMOR COMPOUNDS: MECHANISMS OF ACTION 42.3 FERROCENE AND MEDICINAL CHEMISTRY The synthesis of ferrocene in 1951 by Pauson [86] followed by the elucidation of its structure by Wilkinson et al. [87] and Fischer and Pfab [88] constitutes a significant advance in modern chemistry. Indeed this time period, 1951–1952, marks the beginning of the explosion in transition metal organometallic chemistry. Ferrocene possesses an external structure that resembles that of an aromatic nucleus, it can be easily functionalized, is stable in a nonoxidizing environment, and is consequently well adapted to play the role of substituent in medicinal chemistry [89]. Besides this, it is also lipophilic and compact, and does not fundamentally modify the pharmacological properties of the molecule when it replaces a phenyl unless there are important bioisosteric considerations. In addition, it is not particularly toxic, with oral and LD50 values of 1320 and 500 mg/kg for rat and 832 and 335 mg/kg for mouse [90]. Ferrocene was used very early on to replace functional groups, in particular phenyl moieties, in existing drugs to obtain novel species, with mixed results [91, 92]. Three typical examples are shown in Fig. 42.4. Ferrocenyl derivatives of amphetamine and phenytoin have activity well below that of the parent organic compounds [93]. Those of penicillin and cephalosporin (Fig. 42.5) show activity against drug-resistant bacteria and low toxicity in vivo [94, 95]. Among the undeniable successes can be numbered ferroquine (FQ) synthesized in 1997 by Brocard et al. [96] and presently at the end of phase II clinical trials with Sanofi-Aventis, and the ferrocifen family reported in studies published by us since 1996 [97, 98]. The two products, FQ and OH-Fc (Fig. 42.6), share the characteristic of improving and even revolutionizing an older medication; in the former case, chloroquine, which had become resistant to certain strains of malaria, and in the latter tamoxifen, which can only be used against hormone-dependent breast cancers. It is this latter family of products, effective also on hormone-independent breast cancers, and for which we possess fairly rich data concerning the redox function of ferrocene and its chemical consequences on the local organic framework, that will be discussed in the following [85]. 42.4 SYNTHESIS AND BEHAVIOR OF FERROCIFEN DERIVATIVES The project began with the synthesis of Fc-OH-Tam, 14 (Fig. 42.6), corresponding to the replacement of the β-arene of OH-TAM 12, with a ferrocenyl group and an adjustment of the length of the amino-alkyl chain. These syntheses can be carried out in various ways [97] but the McMurry coupling proved to be the most suitable [98–102]. Ferrocene itself gives NH 2 Fe NH 2 NH H N O O NH H N O O Fe Amphetamine Phenytoin Figure 42.4 Early examples of ferrocenyl modification of drugs. Fe Cephalosporin R O H N N S O CO 2 H O H N N S O CO 2 H R' O H N N O S CO 2 H R O H N N O S CO 2 H O O Fe Penicillin Figure 42.5 Other examples of ferrocenyl modification of drugs. SYNTHESIS AND BEHAVIOR OF FERROCIFEN DERIVATIVES 567 N Cl HN N Chloroquine N Cl HN Fe N Ferroquine, FQ [96] R R ′ R R ′ Fe 11 Tamoxifen R = H, R ′ = O(CH
2 ) 2 NMe 2 OH-Tamoxifen (OH-TAM) R = OH, R ′ = O(CH
2 ) 2 NMe 2
13 Ferrocifen R = H, R ′ = O(CH
2 ) 3 NMe 2 OH-Ferrocifen (Fc-OH-Tam) R = OH, R ′ = O(CH
2 ) 3 NMe 2
[97]
Example of successful ferrocenyl modification of drugs. an IC 50
μM on hormone-independent breast cancer cells (MDA-MB-231) [103], and so hydroxytamoxifen 12 and ferrocene are not viable against hormone-independent breast cancer cells (ER α − ) (Table 42.1). However when the β-aryl group in OH-TAM 12 (IC 50 = 30 μM) is simply replaced by a ferrocenyl entity, inactive in itself, the species 14 is produced with an IC 50 value of 0.5 μM. This immediately changes the paradigm. The optimal length of the carbon chain can be 3 or 4 carbon atoms [100, 101] in Fc-OH-Tam 14. On hormone-dependent (ER α +
meanwhile, the IC 50 values for 12 or 14 remain comparable [103]. Everything occurs as if the presence of the ferrocene preserved the initial properties of 12 while gaining an additional function in 14 that is absent from 12 and only becomes apparent on the cancerous cell. It was quickly discovered that the presence of a basic chain was not absolutely essential for this new property, and this led to 15 with an IC 50 on MDA-MB-231 of 0.6 μM [104] (Table 42.1). The antiestrogenic effect present in 12 is lost but the cytotoxic component linked to the ferrocenyl group is maintained. The IC 50
μM, twice that of 15 which bears two paraphenols. Molecule 17, where the second phenol is in the meta-position and thus cannot form a conjugated bond with the skeleton, gives an IC 50 comparable (1.03 μM) to that of 16 [105]. This is even clearer with 18 where the IC 50 is 3.5 μM [104]. The position and number of OH groups is thus an important element in the cytotoxic effect. If OH is replaced by NH 2
oxidation after hydrolysis, IC 50 values of 0.47 and 0.65 μM are obtained, slightly better than the value for the corresponding phenol [106, 107]. Product 21, differing from 15 in the position of the ferrocenyl entity, which prevents conjugated binding with the organic framework, gives an IC 50 value of 6.0 μM [104]. This demonstrates the importance of both the choice and the positioning of the substituents. The series of compounds 22, 23, and 24 reveals the influence of disrupting the conjugation of the system by incorporating a central sp 3 carbon (IC 50 between 2.8 and 4.1 μM) [108]. The data given above illustrate the importance of the conservation in these series of the [ferrocenyl-conjugate spacer-paraphenol] motif [103]. Electrochemical and electron spin resonance (ESR) studies of species related to 14, 15 and 16 have shown that one of the active metabolites could be an electrophilic quinone methide (QM) such as 25 [109–111] (Fig. 42.7) whose chemical reactivity is currently being elucidated although it is already known that organometallic QMs form 1,8 Michael adducts with various thiols. Table 42.2 summarizes selected biological effects observed in the presence of 1 μM of OH-TAM 12 or Fc-OH-TAM
The open series above produces reactive oxygen species (ROS) on cancerous cells [85, 112, 113] but this is not universally the case as this is not observed with metastatic melanoma cells, yet the cytotoxic effect is still in evidence [114]. The case of melanoma may be an exceptional one as these very exposed cells possess a sophisticated antioxidant system [114]. It should be noted that the presence of antioxidants added into the medium, such as N-acetyl cysteine or vitamin E with
568 THE FERROCIFEN FAMILY AS POTENT AND SELECTIVE ANTITUMOR COMPOUNDS: MECHANISMS OF ACTION TABLE 42.1 Various Effects (Electronic, Substituent, Regiochemical) on IC 50 Values in the Ferrocifen Family Compound
MDA-MB-231, Breast Cancer Cell Line. IC 50 , μM References 12 30 103 Ferrocene >160
103 R R ′ Fe
= OH, R = O(CH 2 ) 3 NMe
2 0 .5 101 15 R = OH, R = OH 0 .6
16 R = OH, R = H 1 .13
105 17 R = OH, R = m-OH 1 .03
105 18 R = H, R = m-OH 3 .5
19 R = NH
2 , R
= H 0 .47 106 20 R = NHAc, R = H 0 .65
106 OH HO Fe 21 6 .0 104 Fe HO OH 22 o-OH 2 .8 108 23 m-OH 4 .1 108 24 p-OH 3 .5 108 O R Fe 25 R = H, OH, O(CH 2 )
NMe 2
Quinone methides (QM).
SYNTHESIS AND BEHAVIOR OF FERROCIFEN DERIVATIVES 569 TABLE 42.2 Biological Effects Observed in the Presence of 1 μM of OH-TAM 12 or Fc-OH-TAM 14 Biological Effect Cell Line OH-TAM 12 Fc-OH-TAM 14 Growth inhibitory effect after 4 days MCF-7 (ER α +
+ + + +
MDA-MB-231 (ER α − ) No effect + + Effect on cell cycle after 48 h MCF-7 Cells accumulate in G0/G1 phase Cells accumulate in G0/G1 phase MDA-MB-231 No effect Cells accumulate in S phase Induction of senescence after 5 days MCF-7 + + + MDA-MB-231 No effect + + ROS production (H 2 O 2 ) after 10 min MCF-7
− − + +
MDA-MB-231 − −
+ + On ER
α + breast cancer cells, Fc-OH-TAM displays an antihormone effect analogous to that of OH-TAM, together with a cytostatic effect. On ER α − breast cancer cells, the cytostatic behavior is the only one expressed. This mechanism is distinct from the nongenomic pathway observed with high dose of OH-TAM. 14 and 15, inhibits the antiproliferative effect [85, 115]. DNA is not the primary target of these compounds [116, 117]. However, the possibility of a partial interaction is observed between the oxidized form of 15 and DNA [116]. Experiments with organometallics other than ferrocene (Ti, Ru, Re) attached to the organic framework below have shown the superiority of the Fc group due no doubt to the good redox capacity of this probe with reversible Fe II /Fe
III oxidation [118–122]. We have also shown that although phenolic products such as 14 and 15 are very active at low concentrations on cancerous cells, antiproliferative activity on healthy cells such as astrocytes [123] or melanocytes [114] can only be obtained using concentrations of ferrocifenyl products in the order of 100–200 times higher ( >100–200 μM) [114] [123]. This was recently confirmed by another laboratory [124]. There is thus a difference, probably in emission of ROS and/or presence of a target protein redox function, within cancer cells that is revealed by the ferrocifens, which have sensitivity to oxidation via the reduced Fe II and good protection via two cyclopentadienyl ligands that form a sandwich and control the selectivity. This illustrates a fundamental difference between Pt complexes and the ferrocifens. Another series of compounds, characterized by an inversion of the position between the ethyl and one of the aryl groups, was synthesized [125] (Fig. 42.8). Of the compounds in this series, 31 is the most active (Table 42.3). It is the only one that can be oxidized by Ag 2 O, while
the others are inactive in these conditions. They also show little activity against MDA-MB-231 cells. This result reinforces the hypothesis of a mechanism of action for the ferrocenyl complexes via formation of QM. In addition, the methoxylated compounds 28, 30, and 31 are less active than the phenolic analogs 27, 29, and 31. This confirms the importance of the phenol function, which is indispensable for the generation of QM. It has been shown that tamoxifen and hydroxytamoxifen metabolize to 3,4-dihydroxytamoxifen [126]. This catechol can be oxidized by enzymes into ortho-quinone, which can react with DNA and proteins. A number of ferrocenyl catchols have been synthesized [127] (Fig. 42.9). The additional presence of the phenolic function improves the antiproliferative activity of the compounds and for certain products such as 37 and 38, their catechol analogs, 34 and 35, are four times more active. All the catechols in Table 42.4, except 38 and 39, are chemically oxidizable to QMs or ortho-quinones. It is also confirmed that the compounds unable to generate quinones, such as 38 and 39, have little activity. Fe
RO Fe
Fe 28 OR Fe OR RO R = H R = Me 29 30 R = H
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