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. 2012 Dec 1:393:36-52.
doi: 10.1016/j.ica.2012.06.007. Epub 2012 Jun 21.

Metallocenes as Target Specific Drugs for Cancer Treatment

Enrique Meléndez  1
Affiliations

Metallocenes as Target Specific Drugs for Cancer Treatment

Enrique Meléndez. Inorganica Chim Acta. .

Abstract

The application use of organometallic compounds into the cancer research was established in the late 1970s by Köpf-Maeir and Köpf. This new research area has been developed for the past thirty years. In the early 1980s, Jaouen and coworkers recognized the potential application of organometallic compounds vectorized with pendant groups that can deliver the drug to certain specific receptors. This is what is called nowdays Target Specific Drugs. This review will focus on metallocenes vectorized with steroids derivatives of hormones, nonsteroidal and selective endrocrine modulator.

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Figures

Figure 1
Figure 1
α- and β-(3-O-R-l7β-O-R′-estradiol)Cr(CO)3 diasteroisomers.
Figure 2
Figure 2
Structures of organometallic-labeled estradiol at the A-ring (left) and 17α-position of the 17β-estradiol.
Figure 3
Figure 3
Structures of 17α-organometallic labeled 17β-estradiol.
Figure 4
Figure 4
Structure of 17α-[(R-C5H4)M(CO)3]-17β-estradiol. M = Mn, Re; R = CH2, C2.
Figure 5
Figure 5
Hydroxytamoxifen (left) and hydroxyferrocifens (right), n = 2–5, 8.
Figure 6
Figure 6
Ferrocifen structure in the Z and E configurations.
Figure 7
Figure 7
Ortep diagrams of Z-1-[4-(2-dimethylaminoethoxy)phenyl]-1(phenyl-2-ferrocenyl-but-1-ene), ferrocifen (top), and E-[4-(2-dimethylaminoethoxy)phenyl]-1(4-hydroxyphenyl-2-ferrocenyl-but-1-ene), bottom. (Z)-4a and (E)-3a numbering adopted by reference and not related to numbering in Table 1. Reproduced with permission of J. Organometallic Chemistry.
Figure 7
Figure 7
Ortep diagrams of Z-1-[4-(2-dimethylaminoethoxy)phenyl]-1(phenyl-2-ferrocenyl-but-1-ene), ferrocifen (top), and E-[4-(2-dimethylaminoethoxy)phenyl]-1(4-hydroxyphenyl-2-ferrocenyl-but-1-ene), bottom. (Z)-4a and (E)-3a numbering adopted by reference and not related to numbering in Table 1. Reproduced with permission of J. Organometallic Chemistry.
Figure 8
Figure 8
Interaction of 2 docked in the ERα LBD, only the aminoacids in the binding pocket are shown. 2 is represented as space-filling model. Reproduced with permission of Dalton Transaction.
Figure 9
Figure 9
Structures of ruthenocifens and CpRe(CO)3–TAM derivatives (left) and titanocifen (right). R1 = OH, R2 = O(CH2)nN(CH3)2 (n = 2, 3, 4, 5, 8) and R1 = OH = R2.
Figure 10
Figure 10
Representation of the interaction of Ti4+ in the ERα LBD. Reproduced with permission of Dalton Transaction.
Figure 11
Figure 11
Hydroxyferrocifens compounds used for the electrochemical study, Fc = ferrocene.
Figure 12
Figure 12
Proposed mechanism for hydroxyferrocifen conversion to quinine methide.
Figure 13
Figure 13
Compound 21a showing there is no H at β position available for the proposed QM (above) mechanism.
Figure 14
Figure 14
Ortep diagrams of compounds 1 (above) and 2 (below). Reproduced with permission of the American Chemical Society.
Figure 15
Figure 15
Solid state structures of 5a, 6 and 8. Reproduced with permission of Organometallics.
Figure 16
Figure 16
Calculated structures of titanocenyl– pregnenolone (18), trans-androsterone (21) and androsterone (22). Reproduced with permission of J. Biol. Inorg. Chem.
Figure 16
Figure 16
Calculated structures of titanocenyl– pregnenolone (18), trans-androsterone (21) and androsterone (22). Reproduced with permission of J. Biol. Inorg. Chem.
Figure 17
Figure 17
Conformations of ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate a) lowest energy conformer b) conformation inside the receptor. Reproduced with permission of Dalton Transaction.
Figure 18
Figure 18
Representation of the interaction of ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate in the ERα LBD. The complex structure is colored violet. Reproduced with permission of Dalton Transaction.
Figure 19
Figure 19
Internalization of Ferrocenoyl-estradiol on MCF-7 breast cancer cell line using Confocal Microscopy after 2 hours of drug exposure - formula image are estradiol ferrocenoylate (of ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate), formula image is the nucleus.
Scheme 1
Scheme 1
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Chart 8
See this image and copyright information in PMC

References

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