Organometallic cyclic polyphenols derived from 1,2-(α-keto tri or tetra methylene) ferrocene show strong antiproliferative activity on hormone-independent breast cancer cells

We have previously shown that achiral ferrocenyl diphenol butene derivatives are strong antitumor agents against both hormone-dependent and -independent breast cancer cell lines. We report now examples of a new series of two planar chiral diphenol derivatives, namely 1,2-[1-[1,1-bis(4-hydroxyphenyl)methylidene]trimethylene] ferrocene (4), and 1,2-[1-[1,1-bis(4-hydroxyphenyl)methylidene]tetramethylene]ferrocene (5). They were prepared under racemic form from a McMurry coupling reaction with 30% and 16% yields, respectively. Compound 5 gave crystals suitable for X-ray structural analysis. Compounds 4 and 5 were tested for ERα and ERβ affinity, lipophilicity, and proliferative/antiproliferative effects against the hormone-dependent breast cancer cell line MCF-7, and the hormone-independent breast cancer cell line MDA-MB-231. Both compounds exhibit better affinity for ERβ (16.4 ± 0.1, and 7.0 ± 0.4, respectively) than for ERα (6.4 ± 0.2, and 6.6 ± 0.2). The test on hormone-independent breast cancer cell line MDA-MB-231 showed that 4 with a 5-membered ring gives an IC50 value of 2.7 μM while with 5 in which the ring has 6 carbons, the value is reduced to IC50 = 1.23 μM.