Synthesis, characterization, and DNA modification induced by a novel Pt-berenil compound with cytotoxic activity

• Published in: Journal of inorganic biochemistry 1996-07, Vol.63 (1), p.57-68
• Main Authors: González, Víctor M., Amo-Ochoa, Pilar, Pérez, JoséM., Fuertes, Miguel A., Masaguer, JoséR., Navarro-Ranninger, Carmen, Alonso, Carlos
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Circular Dichroism; Diminazene - analogs & derivatives; Diminazene - chemical synthesis; Diminazene - chemistry; Diminazene - pharmacology; DNA Adducts - chemistry; DNA, Neoplasm - chemistry; DNA, Neoplasm - drug effects; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Nucleic Acid Conformation - drug effects; Platinum Compounds - chemical synthesis; Platinum Compounds - chemistry; Platinum Compounds - pharmacology; Tumor Cells, Cultured
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/0162-0134(95)00175-1

In the present paper, we show that the reaction of the antitrypanosomatid berenil drug with K 2PtCl 4 resulted in the synthesis of a covalent Pt(II)-berenil compound of formula [Pt 2Cl 4 (berenil) 2]Cl 4·4H 2O as shown by IR, 1H, 13C, and 195Pt-NMR. The Pt-berenil compound was tested for in vitro antitumor activity against HL-60 and U-937 human leukemic cells. The results show that the LC 70 values of the Pt-berenil are about two-fold lower than those of cis-DDP in both HL-60 and U-937 cell lines. Melting data of Pt-berenil:DNA and berenil:DNA complexes indicate that the platinated compound produces on a DNA secondary structure higher compaction than the berenil ligand. The mobility in agarose gels and the circular dichroism spectra of the compounds:DNA complexes revealed, moreover, that both induce drastic changes on a DNA secondary and tertiary structure. The total reflection X-ray fluorescence data showed, in addition, that DNA platination in Pt-berenil:DNA complexes occurs within minutes after addition of the drug, in contrast to what that observed in cis-DDP:DNA complexes. On the basis of these results, we propose that in Pt-berenil, the berenil ligand acts as a carrier of the active cis-P(II) centers towards DNA.