Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

Abstract

We have previously shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via metabolic quinone methide (QM) formation. To further evaluate this proposed mechanism, we have created a series of ferrocenyl prodrugs containing methyl and acetyl-protected thio-and oxo-phenols: 2-ferrocenyl-1,1-bis(4-acetoxyphenyl)-but-1-ene (5), 2-ferrocenyl-1,1-bis(4-thioacetylphenyl)-but-1-ene (6), 2-ferrocenyl-1,1-bis(4-methoxyphenyl)-but-1-ene (7), and 2-ferrocenyl-1,1-bis(4-thiomethylphenyl)-but-1-ene (8), which might be activated by hydrolysis enzymes in situ. Only the acetoxy 5 displayed antiproliferative effects (IC 50 on MDA-MB-231 of 0.5 lM) while 6-8 act as pure estrogens (proliferative on MCF-7 and little to no effect on MDA-MB-231). The behaviour of 5 is similar to that previously found for the free phenol 2-ferrocenyl-1,1-di(4-hydroxyphenyl)-but-1-ene (2), indicating that 5 is metabolized in situ to 2, which could then undergo oxidative QM formation. The observation that the thioacetyl 6 is not cytotoxic suggests that the in situ oxidative chemistry of the putative ferrocenyl thiophenol is different from that of 2. Because p-thioquinone methides are practically unknown, the negative results for 6 further implicate the bioformation of the QM in the case of 2 and related compounds. The lack of cytotoxicity of 7 and 8 can be attributed to lack of efficient hydrolysis in situ. Estrogen receptor binding affinity studies for the compounds and the X-ray structure of 8 are also reported.

Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens, the (cyclobutadiene)cobalt analogues of hydroxytamoxifen

“…This result is in accord with that found for the sandwich or half-sandwich diphenol complexes of ruthenium, rhenium or manganese [26]. It also confirms that even compounds with low RBA values can express a significant estrogenic effect [27]. The aminoalkyl-hydroxycobaltifens, 2g and 2h, direct analogues of tamoxifen and ferrocifen, are weakly cytotoxic towards both cell lines.…”

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:…”

Ferroquine: the antimalarial drug of the future

“…Nos últimos anos esta nova área de pesquisa tem despertado interesse, uma vez que a incorporação de metais de transição à estrutura de uma droga pode acentuar a sua atividade biológica. 22 25,26,27 O ferroceno 12 é um composto estável, 28,29 não-tóxico, 28 que exibe interessantes propriedades de oxiredução, 30 as quais se devem à sua capacidade de sofrer oxidação reversível, com a geração de espécie do tipo cátion-radical -íon ferrocênio 13. 28 14,37,40 Estudos mostraram também que além de não haver resistência cruzada entre a ferroquina e os demais antimaláricos quinolínicos, 40 a atividade de 14 independe das mutações dos genes do P. falciparum, o que não ocorre com a cloroquina.…”