Ferrocifens and Ferrocifenols as New Potential Weapons against Breast Cancer

Abstract

Depending on the presence or absence of the estrogen receptor in the cells, breast cancer today is often treated by endocrine therapy (tamoxifen) or chemotherapy, respectively. We present now a new paradigm for breast cancer treatment, taking advantage of concepts in bioorganometallic chemistry. In this way, we have synthesized molecules containing an organometallic moiety (ferrocene), and a biovector (hydroxytamoxifen), yielding compounds which display a new therapeutic spectrum consisting of antiestrogenicity and cytotoxicity. A structure–activity relationship study has shown that a ferrocene group, linked to a para-phenol group by a conjugated spacer, is a necessary motif for strong cytotoxic effects to be observed.

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

“…This heavy element offers a capacity for good stabilization of certain high degrees of oxidation (+VI) and for an excellent metal-to-ligand back-donation at low oxidation states (+II, +III) leading to more stable complexes than those of Fe or Ru in biological media. The potential of this so far neglected metal in biomedically-oriented organometallic complexes deserves to be better studied especially when comparisons with neighboring series of Fe and Ru are easy to obtain [18,19].…”

Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites

“…[2][3][4][5][6][7][8][9][10][11][12] We have shown that some ferrocene derivatives are very active against cancer cells. The addition of a ferrocenyl moiety to selected polyaromatic phenols, [13][14][15][16] amines, 17,18 amides, 19 and esters 19,20 can potentiate their antiproliferative effects against breast and prostate cancer cells. For example, 4-hydroxytamoxifen, the active metabolite of the breast cancer drug tamoxifen, 21 shows limited cytotoxicity against hormone-refractory breast cancer cells (LC 50 for MDA-MB-231 cells:…”

Side‐Chain Effects on the 1‐(Bis‐aryl‐methylidene)‐[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series

“…[9] We have found that the most effective compounds (IC 50 values less than 1 μM) possess, like 2 and 3, a ferrocene-ene-para-phenol entity. [10,11] The ferrocene appears to act as a stimulus for a mild intramolecular oxidation involving the phenol group, leading to the facile production of quinone methides, the formation, structure, and electrophilic behavior of which we have established. [12][13][14][15] A structure-activity relationship (SAR) study extended to include a number of ferrocene complexes has allowed us to identify another molecule, the cyclic diphenol 4 derived from [3]ferrocenophane, with toxicity on MDA-MB-231 cells that is noticeably greater than that of Fc-diOH (3; IC 50 values of 0.09 μM for 4 vs. 0.6 μM for 3).…”