Metallocenes as Target Specific Drugs for Cancer Treatment

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.

Figure 1

α- and β-(3-O-R-l7β-O-R′-estradiol)Cr(CO)₃ diasteroisomers.

Figure 2

Structures of organometallic-labeled estradiol at the A-ring (left) and 17α-position of the 17β-estradiol.

Figure 3

Structures of 17α-organometallic labeled 17β-estradiol.

Figure 4

Structure of 17α-[(R-C₅H₄)M(CO)₃]-17β-estradiol. M = Mn, Re; R = CH₂, C₂.

Figure 5

Hydroxytamoxifen (left) and hydroxyferrocifens (right), n = 2–5, 8.

Figure 6

Ferrocifen structure in the Z and E configurations.

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

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

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

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

Representation of the interaction of Ti⁴⁺ in the ERα LBD. Reproduced with permission of Dalton Transaction.

Figure 11

Hydroxyferrocifens compounds used for the electrochemical study, Fc = ferrocene.

Figure 12

Proposed mechanism for hydroxyferrocifen conversion to quinine methide.

Figure 13

Compound 21a showing there is no H at β position available for the proposed QM (above) mechanism.

Figure 14

Ortep diagrams of compounds 1 (above) and 2 (below). Reproduced with permission of the American Chemical Society.

Figure 15

Solid state structures of 5a, 6 and 8. Reproduced with permission of Organometallics.

Figure 16

Calculated structures of titanocenyl– pregnenolone (18), trans-androsterone (21) and androsterone (22). Reproduced with permission of J. Biol. Inorg. Chem.

Figure 16

Calculated structures of titanocenyl– pregnenolone (18), trans-androsterone (21) and androsterone (22). Reproduced with permission of J. Biol. Inorg. Chem.

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

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

Internalization of Ferrocenoyl-estradiol on MCF-7 breast cancer cell line using Confocal Microscopy after 2 hours of drug exposure - are estradiol ferrocenoylate (of ferrocenoyl 17β-hydroxy-estra-1,3,5(10)-trien-3-olate), is the nucleus.

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