Synthesis and Biological Studies of Pyrazolyl‐Diamine Pt^II Complexes Containing Polyaromatic DNA‐Binding Groups

Abstract

New [PtCl(pz*NN)](n+) complexes anchored by pyrazolyl-diamine (pz*NN) ligands incorporating anthracenyl or acridine orange DNA-binding groups have been synthesized so as to obtain compounds that would display synergistic effects between platination and intercalation of DNA. Study of their interaction with supercoiled DNA indicated that the anthracenyl-containing complex L(2) Pt displays a covalent type of binding, whereas the acridine orange counterpart L(3) Pt shows a combination of intercalative and covalent binding modes with a strong contribution from the former. L(2) Pt showed a very strong cytotoxic effect on ovarian carcinoma cell lines A2780 and A2780cisR, which are, respectively, sensitive to and resistant to cisplatin. In these cell lines, L(2) Pt is nine to 27 times more cytotoxic than cisplatin. In the sensitive cell line, L(3) Pt showed a cytotoxic activity similar to that of cisplatin, but like L(2) Pt was able significantly to overcome cisplatin cross-resistance. Cell-uptake studies showed that L(2) Pt accumulates preferentially in the cytoplasm, whereas L(3) Pt reaches the cell nucleus more easily, as clearly visualized by time-lapse confocal imaging of live A2870 cells. Altogether, these findings seem to indicate that interaction with biological targets other than DNA might be involved in the mechanism of action of L(2) Pt because this compound, despite having a weaker ability to target the cell nucleus than L(3) Pt, as well as an inferior DNA affinity, is nevertheless more cytotoxic. Furthermore, ultrastructural studies of A2870 cells exposed to L(2) Pt and L(3) Pt revealed that these complexes induce different alterations in cell morphology, thus indicating the involvement of different modes of action in cell death.

Design and Biological Evaluation of New Platinum(II) Complexes Bearing Ligands with DNA-Targeting Ability

“…26 The increase of r i , defined as the molar ratio of added platinum complex per nucleotide, decreases the rate of migration of cc DNA until it comigrates with oc DNA. In this way, a coalescence point (r i = r b (c)) is achieved, which corresponds to the amount of platinum needed for complete removal of all supercoils from DNA.…”

Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA

“…Thus, aminoalkyl-3,6-bis(dimethylamino)acridinium iodide precursors ( 8–10 ), containing three (C 3 ), five (C 5 ) and eight (C 8 ) methylene units, were used as starting materials to obtain both classes of compounds ( Supplementary Figs S1 and S3 ). These acridinium precursors were synthesized following previously described procedures 21 .…”

“…S3 ). The different chelators were synthesized based on methodologies previously described by our group, as detailed in Supplementary Information 21 24 . All 99m Tc-complexes were obtained with radiochemical purity higher than 99%, after RP-HPLC purification to remove the excess of the respective chelators.…”

The key role of coligands in novel ruthenium(II)-cyclopentadienyl bipyridine derivatives: Ranging from non-cytotoxic to highly cytotoxic compounds

“…After a 72 h incubation period the treatment solution was removed, and the cell viability was measured by the MTT assay. [27], * 1.9 ± 0.1 [27], * 110 ± 28 [28], * *Obtained with the same experimental conditions. The TD-DFT intensity was normalized for a better illustration.…”