Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

Abstract

A series of 16 novel diiron complexes of general formula [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(R′)C(R″)CN(R)(Y)}]CF3SO3 (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron μ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH2Ph, R′ = R″ = Me) and 3a (R = CH2CH=CH2, Y = R′ = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV–Vis methods were used to assess the D2O solubility, the stability in aqueous solution at 37 °C and the octanol–water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2–7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R′ = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR).

Tethering Carbohydrates to the Vinyliminium Ligand of Antiproliferative Organometallic Diiron Complexes

“…The formation of the diiron vinyliminium core is not stereoselective, leading to a couple of enantiomers, which were recognized in many crystallographic structures ( Figure 3 ). 13 , 15 , 26 In the present case, the two enantiomers combine with the enantiopure carbohydrate ( Figure 2 ), giving rise to a couple of diastereomers.…”

“… 11 Thus, cationic μ-aminocarbyne complexes ( Figure 1 , structure III ) are accessible by multigram-scale procedures 12 and represent the starting point to obtain vinyliminium derivatives (structure IV ) via CO/alkyne substitution, featured by a notable structural variability. 13 Complexes belonging to the families III ( 14 ) and IV ( 15 ) possess a variable antiproliferative activity related to a multitargeted mechanism of action, with prevalent imbalance of cell redox homeostasis.…”

N-Heterocyclic Carbene Iron Complexes as Anticancer Agents: In Vitro and In Vivo Biological Studies

“…As an extension of the excellent results obtained with metallocenes, half-sandwich iron(II) compounds have received recent attention [ 26 , 27 ]. In particular, diiron carbonyl cyclopentadienyl complexes bearing different co-ligands such as aminocarbyne/iminium [ 28 ] or vinyliminum ligands [ 29 , 30 ] represent a suitable class of organometallic anticancer compounds. They have shown ideal properties such as the presence of a nontoxic metal, appreciable water solubility and amphiphilicity, and stability in aqueous media [ 28 , 29 , 30 ].…”

“…In particular, diiron carbonyl cyclopentadienyl complexes bearing different co-ligands such as aminocarbyne/iminium [ 28 ] or vinyliminum ligands [ 29 , 30 ] represent a suitable class of organometallic anticancer compounds. They have shown ideal properties such as the presence of a nontoxic metal, appreciable water solubility and amphiphilicity, and stability in aqueous media [ 28 , 29 , 30 ]. Despite the intensive research on iron complexes as possible anticancer drugs, the medicinal potential of Fe–NHC complexes has remained almost unexplored [ 31 ].…”

“…Motivated by our interest in developing new effective anticancer metal-based drugs [ 35 , 36 , 37 ] and considering the recent aptitudes of NHC ligands in drug design, the known anticancer activity of iron compounds [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ], and our large experience in Fe–NHC organometallic chemistry [ 38 , 39 , 40 , 41 ], we decided to study the anticancer activity of half-sandwich Fe–NHC compounds. As an NHC, we chose the bulky 1,3-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) ligand.…”