Pt-Fe ferrocenyl compounds with hydroxyquinoline ligands show selective cytotoxicity on highly proliferative cells

• Published in: Journal of inorganic biochemistry Vol. 199; p. 110779
• Main Authors: Rivas, Feriannys, Medeiros, Andrea, Comini, Marcelo, Suescun, Leopoldo, Rodríguez Arce, Esteban, Martins, Marta, Pinheiro, Teresa, Marques, Fernanda, Gambino, Dinorah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2019; Elsevier
• Subjects: Anti-proliferative; Cancer cells; Ferrocenyl compounds; Hydroxyquinoline derivatives; Platinum; Trypanosoma brucei; Ferrocenyl compounds; Anti-proliferative; Trypanosoma brucei; Platinum; Hydroxyquinoline derivatives; Cancer cells
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2019.110779

Searching for a more effective chemotherapy for the treatment of Human African trypanosomiasis, the disease caused by the parasite Trypanosoma brucei, and cancer, in the current work five new [PtII(L)(dppf)](PF6) compounds, with HL = 8-hydroxyquinoline derivatives and dppf = 1,1′-bis(diphenylphosphino)ferrocene, were synthesized and fully characterized. Crystal structures of three compounds were solved by XRD. The compounds displayed fairly good activity against bloodstream T. brucei, with IC50 values in the submicromolar range (IC50: 0.14–0.93 μM), and good selectivity towards the pathogen (SI: 11 - 48) with respect to mammalian macrophages (cell line J774). Coordination to the {Pt-dppf} moiety led, in most cases, to an enhancement of the activity in respect to the bioactive ligands (11 to 41 fold). Cytotoxicity was assessed against wildtype (A2780) and cisplatin-resistance (A2780cisR) ovarian cancer cell lines. Four [PtII(L)(dppf)](PF6) compounds were more active (IC50: 1.2–4.4 μM) than cisplatin (IC50: 26.0 μM) on A2780 cells and showed far superior activity than the reference drug against A2780cisR cells. Platinum levels in A2780 cells showed poor correlation between cellular uptake and the cytotoxic activity. All the complexes interacted with DNA and the most active ones induced reactive oxygen species (ROS) formation which suggested that the mechanism of action for these complexes may be mediated by oxidative stress and interaction with DNA that could act as a potential molecular target for this type of complexes. Some complexes of this series could be considered new hits for the development of prospective agents against trypanosomatid parasites and ovarian cancer.
Platinum bis(diphenylphosphino)ferrocene compounds with 8-hydroxyquinoline derivatives as co-ligands showed improved activities on Trypanosoma brucei and selectivities towards the pathogen in respect to the ligands. Compounds were also cytotoxic on A2780 and A2780cisR cancer cells but poorly selective. Generation of reactive oxygen species was detected. DNA could be a target. [Display omitted]
•Pt heterobimetallic ferrocenyl compounds with hydroxyquinolines were synthesized and characterized.•Compounds showed good activities on bloodstream Trypanosoma brucei.•Activity against T. brucei and selectivity improved in respect to the ligands.•Compounds were cytotoxic on A2780 and A2780cisR cancer cells but low selective.•Compounds generate reactive oxygen species in cancer cells and DNA could be a target.