An important challenge in the field of anticancer chemotherapy is the search for new species
to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to
metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M
(M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at
position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic
pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir >
L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance.
However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal
complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes
interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only
complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2
).
This result supports the hypothesis of a potential dual mechanism consisting of two different chemical
pathways: DNA binding and ROS generation. This behavior provides this complex with a great
effectivity in terms of cytotoxicity
