Mono-, Di- and Tetra-iron Complexes with Selenium or Sulphur Functionalized Vinyliminium Ligands: Synthesis, Structural Characterization and Antiproliferative Activity

Abstract

A series of diiron/tetrairon compounds containing a S- or a Se-function (2a–d, 4a–d, 5a–b, 6), and the monoiron [FeCp(CO){SeC1(NMe2)C2HC3(Me)}] (3) were prepared from the diiron μ-vinyliminium precursors [Fe2Cp2(CO)( μ-CO){μ-η1: η3-C3(R’)C2HC1N(Me)(R)}]CF3SO3 (R = R’ = Me, 1a; R = 2,6-C6H3Me2 = Xyl, R’ = Ph, 1b; R = Xyl, R’ = CH2OH, 1c), via treatment with S8 or gray selenium. The new compounds were characterized by elemental analysis, IR and multinuclear NMR spectroscopy, and structural aspects were further elucidated by DFT calculations. The unprecedented metallacyclic structure of 3 was ascertained by single crystal X-ray diffraction. The air-stable compounds (3, 4a–d, 5a–b, 6) display fair to good stability in aqueous media, and thus were assessed for their cytotoxic activity towards A2780, A2780cisR, and HEK-293 cell lines. Cyclic voltammetry, ROS production and NADH oxidation studies were carried out on selected compounds to give insights into their mode of action.

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

“…III ) L=imidazole or N‐substituted imidazole, X=CF 3 SO 3 (2013); [11d] L=carbohydrate‐substituted nitrile, X=PF 6 (2015); [11a] L=N‐heteroaromatic nitrile, X=PF 6 or CF 3 SO 3 (2014) [11b] . IV ) R=Me, CH 2 Ph or 2,6‐C 6 H 3 Me 2 (Xyl), R′=alkyl, aryl, pyridyl, or thiophenyl, Y=H, Ph or S/Se group (2019, 2020) [17a,b] …”

“… [11b] IV ) R=Me, CH 2 Ph or 2,6‐C 6 H 3 Me 2 (Xyl), R′=alkyl, aryl, pyridyl, or thiophenyl, Y=H, Ph or S/Se group (2019, 2020). [ 17a , 17b ]…”

Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

“…Such a mode of action strikingly differs from that of platinum compounds, which instead induce cell death through DNA binding [ 10 , 30 ]. On the wave of our longtime experience with organo-iron synthetic chemistry [ 31 , 32 , 33 , 34 , 35 ], in the very last years we have contributed to unveil the anticancer potential of diiron complexes, which was almost unexplored [ 36 , 37 , 38 , 39 , 40 ]. This is surprising, in that diiron complexes hold a major advantage, compared to related monoiron species, due to the presence of adjacent metal atoms “working in concert”, thus allowing the easy construction and the stabilization of uncommon bridging ligands and the co-presence of other ligands [ 31 , 41 , 42 , 43 ].…”

“…Cationic complexes of type III ( Figure 1 ), containing a tightly coordinated bridging vinyliminium ligand, originate from the stepwise coupling of one isocyanide with one alkyne [ 44 ]. Complexes III are rather stable in aqueous media and display a variable cytotoxicity, ranging from the micromolar range to inactivity; they appear to exert their action following the general behavior shown by cytotoxic iron compounds, i.e., through the interference with redox processes [ 36 , 37 , 38 , 39 , 40 , 45 ]. Notwithstanding, other ways that are not accessible to ferrocene derivatives might be viable, including binding to biological targets [ 36 , 37 , 38 , 39 ] and the auxiliary effect of slow carbon monoxide release [ 37 , 40 , 45 ].…”

“…Complexes III are rather stable in aqueous media and display a variable cytotoxicity, ranging from the micromolar range to inactivity; they appear to exert their action following the general behavior shown by cytotoxic iron compounds, i.e., through the interference with redox processes [ 36 , 37 , 38 , 39 , 40 , 45 ]. Notwithstanding, other ways that are not accessible to ferrocene derivatives might be viable, including binding to biological targets [ 36 , 37 , 38 , 39 ] and the auxiliary effect of slow carbon monoxide release [ 37 , 40 , 45 ]. The structural diversity offered by the choice of the isocyanide (R substituent) and alkyne (R′, R″) reagents enables to tune important physico-chemical properties of the complexes (e.g., water solubility, amphiphilicity), correlated to their activity.…”