Examples where introduction of ferrocene has resulted in enhanced activity or a change in activity profile

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The replacement of one of the phenyl rings in tamoxifen by ferrocene has given rise to a group of compounds called ferrocifens.24,25,26 Tamoxifen is a selective estrogen receptor modulator that is used against breast cancer. Its activity is limited to 'estrogen receptor positive' tumours that constitute about 60% of breast cancer cases. The ferrocifens were synthesized in an attempt to overcome the shortcomings of tamoxifen as an anti-tumour agent. The triphenylethylene-like framework of tamoxifen is retained in the ferrocifens in order to ensure recognition for the estradiol receptor. The ferrocene ring was included in order to take advantage of the eventual formation of the ferrocenium ion (in which the iron is in its Fe3+ state) on metabolism.24 The ferrocenium ion is known to

Fluconazole

Fluconazole be cytotoxic and it was postulated that combining anti-estrogenic and cytotoxic activities in the ferrocifens would be an advantageous strategy.

O(CH2)2N(CH3)2

R= H: Tamoxifen (Z+ E) R = OH: Hydroxytamoxifen (Z+E)

CH3CH

CH3CH

5:

R

=H;

X =

O(CH2)2N(CH3)2

6:

R

= OH;

X =

O(CH2)2N(CH3)2

7:

R

= OH;

X =

O(CH2)3N(CH3)2

8:

R

= OH;

X =

O(CH2)4N(CH3)2

9:

R

= OH;

X =

H

Compounds 5-9 are some of the ferrocifens that have been reported in the literature. The ferrocifen 5 bears the closest resemblance to tamoxifen. The hydroxy ferrocifen 6 is meant to mimic hydroxytamoxifen, the active metabolite of tamoxifen. Compounds 7 and 8 are homologues of 6, in which the basic dimethylami-noalkoxy side chain is extended from ethyl (6, n = 2) to propyl (7) and butyl (8). In ferrocifen 9, the basic side chain is omitted altogether. Some interesting structure-activity relationships are revealed. First, the presence of the bulky ferrocene ring diminished the affinity of the ferrocifens for the estrogen receptor.24,25,26 Radio-ligand displacement assays using tritiated estradiol and sheep uterine cytosol as a

source of estrogen receptors showed that binding affinity of hydroxytamoxifen (Z-isomer) decreased from 107% (estradiol = 100%) to 40% (in 6, Z-isomer) upon introduction of ferrocene.26 Increasing the chain length of the basic side chain also adversely affected binding affinity: 11.5% for 7 (E + Z) compared to 38.5% for hydroxytamoxifen (E + Z). Second, despite their diminished affinities for the estrogen receptor, the ferrocifens (6, 7, 8) were able to inhibit the growth of a human breast cancer cell line (MCF-7, estrogen receptor positive) to almost the same extent as tamoxifen.24,25,26 The observation that estradiol abolished the anti-proliferative effect of 8 suggested that the ferrocifens were interacting at the same site as estrogen in these cells.25 Moreover, ferrocifen 9 (no basic side chain) and unsubstituted ferrocene had greatly diminished activity, an indication that the tamoxifen template is largely responsible for interaction with the estrogen receptor, as anticipated.25 Interestingly, the length of the basic side chain determined if the ferrocifens interacted with the receptor as an agonist or antagonist. Thus, ferrocifen 6 caused estrogen-dependent tumour T47-D xenografts in nude mice to increase in size but lengthening the side chain to give higher homologues 7 and 8 restored anti-estrogenic activity.25 The observation that ferrocifen 6 had estrogenic activity but could still inhibit the growth of breast cancer cells appears to be contradictory. The authors proposed that the addition of the ferrocene ring introduces a genotoxic component that is absent in tamoxifen. Ferrocifens 5 and 6 do indeed induce lesions in the DNA of MCF-7 cells.26 It is possible that the anti-proliferative effect of 6 is due to its greater genotoxic effect compared to its estrogenic activity. These results support the original hypothesis that the tamoxifen-like framework in ferro-cifens confers recognition for the estrogen receptor while the presence of ferrocene induces damage to DNA, possibly via reactive oxygen species generated in a Fenton-like reaction involving the Fe2+/Fe3+ couple.27,28

Possibly the best known example of a successful ferrocene-phenyl/alkyl substitution is that of the ferrocene analogue of the anti-malarial agent chloro-quine-ferrochloroquine, also known as ferroquine. There is a strong likelihood that ferrochloroquine will eventually be used for the treatment of human malaria. Thus the development of ferrochloroquine will be discussed in detail in the following section.

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