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Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells

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 c...

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Autores principales: Schleser, Sebastian W., Krytovych, Oleksandr, Ziegelmeier, Tim, Groß, Elisabeth, Kasparkova, Jana, Brabec, Viktor, Weber, Thomas, Schobert, Rainer, Mueller, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10343763/
https://www.ncbi.nlm.nih.gov/pubmed/37446835
http://dx.doi.org/10.3390/molecules28135173
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author Schleser, Sebastian W.
Krytovych, Oleksandr
Ziegelmeier, Tim
Groß, Elisabeth
Kasparkova, Jana
Brabec, Viktor
Weber, Thomas
Schobert, Rainer
Mueller, Thomas
author_facet Schleser, Sebastian W.
Krytovych, Oleksandr
Ziegelmeier, Tim
Groß, Elisabeth
Kasparkova, Jana
Brabec, Viktor
Weber, Thomas
Schobert, Rainer
Mueller, Thomas
author_sort Schleser, Sebastian W.
collection PubMed
description 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(PPh(3))(2)]Pt/Pd fragment attached to atom C-8 via formal η(1)-sigma or η(2)-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 IC(50) 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.
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spelling pubmed-103437632023-07-14 Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells Schleser, Sebastian W. Krytovych, Oleksandr Ziegelmeier, Tim Groß, Elisabeth Kasparkova, Jana Brabec, Viktor Weber, Thomas Schobert, Rainer Mueller, Thomas Molecules Article 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(PPh(3))(2)]Pt/Pd fragment attached to atom C-8 via formal η(1)-sigma or η(2)-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 IC(50) 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. MDPI 2023-07-02 /pmc/articles/PMC10343763/ /pubmed/37446835 http://dx.doi.org/10.3390/molecules28135173 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schleser, Sebastian W.
Krytovych, Oleksandr
Ziegelmeier, Tim
Groß, Elisabeth
Kasparkova, Jana
Brabec, Viktor
Weber, Thomas
Schobert, Rainer
Mueller, Thomas
Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
title Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
title_full Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
title_fullStr Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
title_full_unstemmed Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
title_short Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells
title_sort palladium and platinum complexes of the antimetabolite fludarabine with vastly enhanced selectivity for tumour over non-malignant cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10343763/
https://www.ncbi.nlm.nih.gov/pubmed/37446835
http://dx.doi.org/10.3390/molecules28135173
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