Supramolecular Iron Cylinder with Unprecedented DNA Binding Is a Potent Cytostatic and Apoptotic Agent without Exhibiting Genotoxicity

Abstract

The supramolecular iron cylinder, [Fe(2)L(3)]Cl(4) (L = C(25)H(20)N(4)), shows unprecedented DNA binding in vitro, inducing intramolecular DNA coiling and also targeting Y-shaped DNA junctions. We investigated its effects on proliferation and survival in both tumor and normal cell lines. Iron cylinder reduced mitochondrial activity of cultures with potency similar to cisplatin, inhibited the cell cycle, and increased cell death by apoptosis. Associated with this, we observed a lowering of the association of propidium iodide with cellular DNA consistent with an observed competitive displacement of PI from naked DNA by cylinders. Importantly, and in contrast to existing anticancer drugs such as cisplatin, the iron cylinder [Fe(2)L(3)](4+) was not genotoxic. In summary, the design of metal complexes such as [Fe(2)L(3)](4+) with potential anticancer properties in the absence of genotoxicity may represent a significant step toward therapeutic advancement.

Recognition of DNA bulges by dinuclear iron(II) metallosupramolecular helicates

“…Metallo-supramolecular chemistry has been used to generate cationic supramolecular helicates possessing promising anticancer and antimicrobial activity, and it has been hypothesized that binding to DNA is responsible for this behavior [14][15][16][17] Fig. 1) bind strongly and noncovalently in the major groove, causing remarkable intramolecular coiling of DNA and extensive DNA unwinding [18,19], and show preferential binding to regular alternating purine-pyrimidine sequences [20].…”

Targeting Higher‐Order DNA: Beyond the G‐Quadruplex

“…The complex had antitumour activity in the low micromolar range (IC 50 18-52 mm) across a range of cell lines but did not induce strand breaks in DNA and was not genotoxic. [15] Blockage of the cell cycle in G 0 /G 1 such that the number of cells in S phase decreased was also observed, along with cell death by the programmed cell death pathway. It is possible that the binding of the compound to the three-way junction that is formed by the replication fork is leading to an inhibition of proliferation and to the observed effects, but this remains to be verified by further experiments.…”

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…Recent proofof-principle studies on organometallic NHC anticancer agents showed that this class of compounds is able to target several canonical and non-canonical DNA secondary structures. In detail, metal NHC complexes were shown to interact with duplex, mismatched and Gquadruplex DNA, while examples of other classes of metal-based anticancer agents exist that inhibit replication forks, 89 by interacting with DNA three-way junctions, 90 spectroscopy and isotope-specific mass spectrometry would allow to follow not only the compounds distribution in cells, but also the structural integrity of the compound, e.g. with regard to ligand exchange reactions.…”