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

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 ]CF 3 SO 3 , afforded novel diiron complexes with a bridging vinyliminium ligand, [ 2 – 10 ]CF 3 SO 3 , 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 D 2 O solubility, stability in D 2 O 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.

Tethering Carbohydrates to the Vinyliminium Ligand of Antiproliferative Organometallic Diiron Complexes

“…The presence of a carbohydrate unit does not seem beneficial to the uptake, and a passive diffusion pathway could be hypothesized for the less hydrophilic complexes, but more studies are required to validate this hypothesis. In agreement with the previous reports, it is presumable that the cytotoxicity is triggered mainly by the intracellular disassembly of the diiron scaffold, 7 , 15 , 17 with the release of iron(I) ions contributing to the imbalance of the cell redox homeostasis. 14 , 32 In this regard, the complete inactivity of the highly unstable complex [ 2 ]CF 3 SO 3 agrees in that, to supply an antiproliferative effect, the degradation must be operative inside the cell.…”

“… 26 , 27 The Cp rings were seen as singlets in the range 5.06–5.74 ppm, which is indicative of a cis arrangement, upon comparison with a library of data available for homologous non glycosylated complexes. 13 , 15 , 17 , 26 Moreover, the unequal iminium substituents in [ 3b ]CF 3 SO 3 and [ 5b ]CF 3 SO 3 (R = Xyl) adopt the E geometry. Instead, [ 6b ]CF 3 SO 3 exists as a mixture of E and Z isomers (additional Cp resonance at 4.83 ppm), with large prevalence of the former.…”

“… 16 Recently, we applied this approach to obtain diiron vinyliminium complexes IV derivatized with aspirin and chlorambucil, showing a clear influence of the bioactive moiety on the cytotoxicity profiles of the resulting complexes. 17 …”

“…A general strategy to optimize the activity of anticancer metal complexes consists in the attachment of an organic fragment with documented biological activity to the metal scaffold . Recently, we applied this approach to obtain diiron vinyliminium complexes IV derivatized with aspirin and chlorambucil, showing a clear influence of the bioactive moiety on the cytotoxicity profiles of the resulting complexes …”

Diversity-oriented synthesis and bioactivity evaluation of N-substituted ferrocifen compounds as novel antiproliferative agents against TNBC cancer cells

“…[10][11][12][13][14] A number of series of transition metal organometallic complexes have been explored in an attempt to treat malignant tumors, including those of Ru, Os, Au, Ir, Ti, as well as of Fe, which is the most abundant transition metal in the human body. [15][16][17][18][19][20] In the latter case, the iron is generally present as a ferrocenyl moiety, whereby it can be stabilized as Fe(II) in a non-oxidizing medium.…”