Antiproliferative and bactericidal activity of diiron and monoiron cyclopentadienyl carbonyl complexes comprising a vinyl‐aminoalkylidene unit

Abstract

A series of diiron complexes with two cyclopentadienyls, two carbonyls, and one bridging vinyl-aminoalkylidene as ligands, [3a-h]CF 3 SO 3 and [4a-d] CF 3 SO 3 , was synthesized in 66-94% yields from diiron μ-aminocarbyne precursors. The subsequent reactions with pyrrolidine led to selective fragmentation to aminoalkylidene-ferracyclopentenone derivatives (5a-h and 6a-c) in 30-84% yields. The compounds were characterized by elemental analysis, Fourier transform infrared and NMR spectroscopy, and by single crystal X-ray diffraction in three cases. The stability in aqueous media relevant to biological trials, the carbon monoxide release, and the catalytic activity in NADH oxidation were evaluated for selected compounds by NMR spectroscopy and gas chromatography. The in vitro antiproliferative activity of the compounds was determined towards cancer (A2780, A2780cisR) and noncancer (HEK-293) cell lines. Moreover, the antibacterial activity was tested on Gram-positive (vancomycin-resistant E. faecium and methicillin-resistant S. aureus) and Gram-negative strains (A. baumannii and P. aeruginosa). K E Y W O R D S amino-alkylidene ligand, bioorganometallic chemistry, cytotoxic and antibacterial activity, diiron complexes, iron-carbonyl complexes Dalila Rocco and Natalia Busto contributed equally to the work.

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

“…These results attest the power of the novel diiron complexes to release CO in cellular milieu and, more importantly, could at least in part explain the tumour‐selective cytotoxic effect exerted by [ 2C ]CF 3 SO 3 and [ 2D ]CF 3 SO 3 . Note that the ability of a range of related diiron cyclopentadienyl complexes to release CO ligands in aqueous environments was previously demonstrated [16a,39] . The relatively fast release of carbon monoxide within the cell might be associated to the presence of a consistent amount and variety of biological substrates, which can quicken the formation of CO substitution diiron products.…”

“…Note that the ability of a range of related diiron cyclopentadienyl complexes to release CO ligands in aqueous environments was previously demonstrated. [ 16a , 39 ] The relatively fast release of carbon monoxide within the cell might be associated to the presence of a consistent amount and variety of biological substrates, which can quicken the formation of CO substitution diiron products. As a matter of fact, it is well documented that [ 2E – F ]CF 3 SO 3 are susceptible to replacement of one terminal CO ligand by suitable C‐, P‐, S‐ and N‐donors to give adducts of general formula [Fe 2 Cp 2 (CO)(L)(μ‐CO){μ‐CNR(Me)}] 0/+ .…”

Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

“…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.…”

Tetrasubstituted Selenophenes from the Stepwise Assembly of Molecular Fragments on a Diiron Frame and Final Cleavage of a Bridging Alkylidene

“…In the last 15 years, some of us have been deeply involved with the versatile chemistry of diiron μ-vinyliminium complexes ([ 2a – d ]CF 3 SO 3 in Scheme 1 ), which can be expeditiously prepared on the gram/multigram scale from [Fe 2 Cp 2 (CO) 4 ]. 7a , 7b , 16 In the framework of our interest in the development of bis-cyclopentadienyl diiron complexes as potential anticancer drugs 17 and on account of the relevance of the selenophene moiety in medicinal chemistry, 18 we exploited the derivatization potential of the vinyliminium ligand in preparing selenophene-decorated ligands, connected to the two iron atoms through a bridging Fischer alkylidene carbon ( 4a – j in Scheme 1 ). In view of the biological studies, we preliminarily probed the stability of 4a in the presence of water and, surprisingly, in this condition we observed the facile release of the functionalized ligand.…”