A Strategy to Conjugate Bioactive Fragments to Cytotoxic Diiron Bis(cyclopentadienyl) Complexes.

Silvia Schoch,Stefano Zacchini,Federica Chiellini,Fabio Marchetti,M Lúcia M F S Saraiva,Tarita Biver,Guido Pampaloni,Simona Braccini,Sarah A P Pereira,Paul J Dyson,Mouna Hadiji

doi:10.1021/acs.organomet.1c00270

Abstract

A series of bioactive molecules were synthesized from the condensation of aspirin or chlorambucil with terminal alkynes bearing alcohol or amine substituents. Insertion of the resulting alkynes into the iron–carbyne bond of readily accessible diiron bis(cyclopentadienyl) μ-aminocarbyne complexes, [1a,b]CF3SO3, afforded novel diiron complexes with a bridging vinyliminium ligand, [2–10]CF3SO3, functionalized with a bioactive moiety. All compounds were characterized by elemental analysis and IR and multinuclear NMR spectroscopy and in three cases by single-crystal X-ray diffraction. Moreover, the D2O solubility, stability in D2O and cell culture media, and octanol–water partition coefficients of diiron complexes were determined spectroscopically. The cytotoxicity of the complexes was assessed in the tumorigenic A2780 and A2780cisR and the nontumorigenic HEK 293T cell lines. Some complexes exhibit high potency and the ability to overcome resistance in A2780cisR cells (aspirin complexes) or high selectivity relative to HEK 293T cells (chlorambucil complexes). Further studies indicate that the complexes significantly trigger intracellular ROS production, irrespective of the nature of the bioactive fragment. DNA alkylation and protein binding studies were also undertaken.

Highlights

We reported a variety of cationic diiron vinyliminium compounds that are cytotoxic against A2780 and A2780cisR cell lines, with IC50 values spanning from nanomolar concentrations to inactivity, depending on the substituents.11−13 According to preliminary studies, the mode of action seems multitargeted, involving ROS production
Ferrocenes in particular, have aroused great interest due to their anticancer properties, while diiron complexes have been much less investigated despite the advantageous cooperative effects provided by two iron centers
The readily accessible {Fe2Cp2(CO)2} scaffold offers considerable opportunities for the construction of various bridging hydrocarbyl ligands, and here we show that bioactive carboxylic acids can be incorporated through an alkyne-insertion reaction

Summary

Introduction

Compounds based on other transition metals have been widely investigated for their anticancer potential.. Compounds based on other transition metals have been widely investigated for their anticancer potential.2 In this context, iron has emerged as an attractive element, being bioessential and basically nontoxic in many forms, and especially ferrocifens, resulting from the conjugation of the ferrocene skeleton with the drug tamoxifen, hold much promise.. The assessment of the anticancer properties of diiron complexes still remains undeveloped, despite opportunities offered by the cooperativity of two metal centers.. We reported a variety of cationic diiron vinyliminium compounds that are cytotoxic against A2780 and A2780cisR cell lines, with IC50 values spanning from nanomolar concentrations to inactivity, depending on the substituents.− According to preliminary studies, the mode of action seems multitargeted, involving ROS production. Antiproliferative activity is maintained in neutral derivatives containing a modified vinyliminium chain.

Methods

Results

Conclusion