The beneficial effect of cyclohexyl substituent on the in vitro anticancer activity of diiron vinyliminium complexes

Abstract

Novel diiron vinyliminium complexes, [Fe₂Cp₂(CO)(μ-CO){μ-η¹:η³-C(R³)CHCNMe(R²)}]CF₃SO₃ (2a–f; R² = 4-C₆H₄OMe, Cy or Me; R³ = Cy, CH₂Cy or 4-C₆H₄OMe; Cy = cyclohexyl, Cp = η⁵-C₅H₅), were synthesized by alkyne insertion reaction from the corresponding diiron aminocarbyne precursors, and isolated in 53–98% yields. The reactions of selected vinyliminium complexes with N₂CHCO₂Et and MeONa, followed by N-methylation, afforded the new hydrazone-vinyliminium [Fe₂Cp₂(CO)(μ-CO){μ-η¹:η³-C(R³)C(NMeNCHCO₂Et)CN(R¹)(R²)}]X (4a–c; R¹ = Me or CH₂Ph; R² = Cy, CH₂Ph or Me; R³ = 4-C₆H₄OMe or Ph; X = NO₃ or CF₃SO₃), in 53–67% yields. Compounds 2a–f and 4a–c were fully characterized by IR and multinuclear NMR spectroscopy, and the structures of 2a–c were ascertained by single crystal X-ray diffraction. Moreover, D₂O solubility, Log P_ow coefficients and the fraction of each complex preserved in aqueous media after 72 hours at 37 °C were determined by ¹H NMR and UV-Vis methods. The antiproliferative activity of 2a–f and 4a–c was measured on the mouse colon CT26 and human glioblastoma U87 cancer cell lines, and on the retinal pigment epithelial RPE-1 non-cancerous cell line. Complexes 2a,d,e, which all bear R³ = Cy, stand out for their performance and their selectivity towards cancer cells. To give insight into the mechanism of action, the effect of 2a, 2d, 2e, 2f, 4b and 4c on the mitochondrial respiration was evaluated in CT26 cells (Seahorse Mito stress test), revealing a correlation between the effectiveness of the complexes and their influence on the mitochondrial metabolism.