Formation of Cisplatin Adducts with the Epigenetically Relevant Nucleobase 5‐Methylcytosine

With about 4 % abundance in the genome 5‐methylcytosine (5mC) is one of the most important epigenetic modifications. Change in DNA hypermethylation levels has even been linked to resistances to cisplatin treatment of cancer cells. This work aimed at the synthesis and full characterization of 5mC‐cis...

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Bibliographic Details
Published in:European journal of inorganic chemistry 2021-01, Vol.2021 (1), p.30-36
Main Authors: Menke, Annika, Dubini, Romeo C. A., Mayer, Peter, Rovó, Petra, Daumann, Lena J.
Format: Article
Language:English
Subjects:
5‐Methylcytosine
Adducts
Ammonia
Antitumor agents
Chemotherapy
Cisplatin
Complex formation
Crystal structure
Deoxyribonucleic acid
Dimers
DNA
Inorganic chemistry
Mass spectrometry
NMR spectroscopy
Platinum
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Summary:With about 4 % abundance in the genome 5‐methylcytosine (5mC) is one of the most important epigenetic modifications. Change in DNA hypermethylation levels has even been linked to resistances to cisplatin treatment of cancer cells. This work aimed at the synthesis and full characterization of 5mC‐cisplatin adducts as well as for the examination of possible side‐reactions and transformations. We report the first X‐ray crystal structure of a cis‐[PtCl(5mC)(NH3)2]Cl complex and the formation of [PtCl(5mC)(NH3)2]+ and [PtCl(5mC)2(NH3)]+ with HR‐ESI mass spectrometry. Further, we explore complex formation and dynamics using 1H, 195Pt, and DOSY NMR spectroscopy. UV/Vis absorption and EPR spectroscopy also confirmed the formation of trace amounts of paramagnetic Pt‐blue species. In the process, a hemiprotonated 5mC dimer, 5mC‐5mCH+, reminiscent of the “i‐motif” in DNA tetramers, was structurally characterized. The complexity of cisplatin‐nucleobase chemistry: Identification of a cisplatin‐5‐methylcytosine complex cis‐[PtCl(5mC)(NH3)2]Cl out of a pool of complex mixtures. Using 1H, 195Pt, DOSY NMR spectroscopy, HR‐MS spectrometry as well as EPR and UV/Vis spectroscopy, multiple products obtained after the reaction of cisplatin with 5mC were characterized.
ISSN:1434-1948
1099-0682
DOI:10.1002/ejic.202000898