Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
Sebastian W. Schleser,
Oleksandr Krytovych,
Tim Ziegelmeier,
Elisabeth Groß,
Jana Kasparkova,
Viktor Brabec,
Thomas Weber,
Rainer Schobert,
Thomas Mueller
Affiliations
Sebastian W. Schleser
Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany
Oleksandr Krytovych
Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany
Tim Ziegelmeier
Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany
Elisabeth Groß
University Clinic for Internal Medicine IV, Hematology/Oncology, Medical Faculty, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
Jana Kasparkova
Department of Biophysics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
Viktor Brabec
Department of Biophysics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
Thomas Weber
University Clinic for Internal Medicine IV, Hematology/Oncology, Medical Faculty, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
Rainer Schobert
Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany
Thomas Mueller
University Clinic for Internal Medicine IV, Hematology/Oncology, Medical Faculty, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a trans-[Br(PPh3)2]Pt/Pd fragment attached to atom C-8 via formal η1-sigma or η2-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC50 values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine.
