Abstract
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.
Highlights
The acquired or intrinsic resistance of standard drugs is a major challenge in cancer treatment [1]
The proligands HL1–HL4 and the complexes were fully characterized by elemental analysis, mass spectrometry, IR and 16096 Hz (1 H) and 13 C{1 H} NMR spectroscopy
We propose that the signals for HL4 are broad, because the free ligand is interacting with species of the type [Cp*IrZ3 ]n+ (Z = H2 O or DMSO) [115]
Summary
The acquired or intrinsic resistance of standard drugs is a major challenge in cancer treatment [1]. Several ruthenium complexes, such as the octahedral NAMI-A [23] or sodium trans-tetra-chloridobis(1Hindazole)ruthenate(III) (IT-139) [15,24,25,26] complexes as well as arene-Ru(II) derivatives of the RAPTA family [27,28,29,30], containing the PTA ligand, or RM175 [31,32], have been. Pharmaceutics 2021, 13, 1540 complexes, such as the octahedral NAMI-A [23] or sodium trans-tetra-chloridobis(1Hof 26 dazole)ruthenate(III) (IT-139) [15,24,25,26] complexes as well as arene-Ru(II) 2derivatives the RAPTA family [27,28,29,30], containing the PTA ligand, or RM175 [31,32], have been ev uated as chemotherapeutic agents in clinical trials (see Figure 1). B a phase I/II study, the clinical activity of NAMI-A was found to be disappointing [33]
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