Naphthalimide-Tagged Ruthenium–Arene Anticancer Complexes: Combining Coordination with Intercalation

Abstract

Ruthenium(II) arene compounds have been modified with the naphthalimide group, tethered via the arene ligand, i.e. {dichloro[η6-N-(phenylalkyl)(4-dimethylamino)-1,8-naphthalimide](pta)ruthenium(II)} (alkyl = methyl, ethyl, propyl, pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), or via an imidazole group, i.e. {dichloro(η6-arene)(N-[3-(imidazol-1-yl)propyl]-1,8-naphthalimide)ruthenium(II)} (arene = p-cymene, toluene). All the compounds are reasonably cytotoxic (ca. 2–49 μM) toward cancer cells, and the arene-linked compounds also display selectivity in that they are less cytotoxic toward model healthy cells. Mechanistic studies show that the ruthenium center does not readily react with DNA but preferentially binds to proteins. In contrast, the naphthalimide group is a strong DNA intercalator, and combined, the complexes might be expected to simultaneously cross-link DNA and proteins.

The development of RAPTA compounds for the treatment of tumors

“…The impact of the complex on cell viability was studied against TS/A and HBL- Figure 11. Functionalization of the arene ligand of RAPTA compounds with anthracene (top) [52], pyrene (center) [53] and naphthalimide (bottom) [54].…”

“…In cytotoxicity assays against the A549, A2780, A2780cisR, Me300 and HeLa cell lines The naphthalimide functionality, a known DNA intercalator [56], was introduced to the arene ligand of the RAPTA structure via short alkyl-chain tethers ( Figure 11, structure (28)) [54]. These complexes undergo aquation on the same timeframe as RAPTA-C and they exhibited high cytotoxicity (72 h) towards the A2780 and the rapid coordination of the ruthenium center to ubiquitin, it was postulated that the high cytotoxicity of these compounds could be related to simultaneous intercalation M a n u s c r i p t 29 of the naphthalimide moiety with DNA and coordination of the ruthenium ion to protein -essentially forming DNA-protein crosslinks.…”

Ruthenium(II)-arene complexes with naphthalimide-tagged N,O- and N,N-chelating ligands: Synthesis and biological evaluation

“…In general, significant hypochromism and large red shifts of the absorption spectral bands are characteristics of compounds that interact with DNA by a strong intercalative mode [56][57][58][59]. The observed hypochromism in the spectra of CT-DNA upon addition of 2a and/or 2b can be partially evidenced as binding via intercalation through the naphthalimide part; as DNA intercalators, in general, leads to a hypochromic effect [29,36]. However, the observed low hypochromism with no red shift in the band position could also suggest an electrostatic mode of DNA binding of the ligands and the new metal complexes.…”

“…In recent years, research on targeted and multifunctional ruthenium(II)-arene complexes tethered to biologically active ligands have received increasing attention, mainly due to the potential synergism that could be achieved by combining a metal ion and a bioactive ligand [1,[27][28][29][30]. It has been noted that tethering of biologically active ligands to the metal ion increases the biological potency of the complexes, through a combination of increased solubility, altered mechanisms of action, increased uptake, and improved cancer targeting properties.…”

“…Dyson and co-workers have recently prepared new half-sandwich ruthenium(II)-arene complexes that incorporate the bioactive 1,8-naphthalimde-tagged arene and imidazole based ligands and,-which exhibited significantly higher anticancer activities compared to the prototype [(η 6 -arene)RuCl 2 (pta)] (pta = 1,3,5-triaza-7-phosphaadmantane) complexes. The higher cytotoxic activity of these new complexes is attributed to the incorporation of the 1,8-naphthalimide moiety onto the ruthenium(II)-arene unit, which provides multi-targeting properties including strong DNA-binding and interaction with proteins [29].…”