title: 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.
authors.affiliation: Instituto Superior Técnico, Instituto Tecnológico e Nuclear, Unidade de Ciências Químicas e Radiofarmacêuticas, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Gama
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.forename: Teresa
authors.initials: T
authors.lastname: Esteves
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques
authors.forename: António
authors.initials: A
authors.lastname: Matos
authors.forename: José
authors.initials: J
authors.lastname: Rino
authors.forename: Joana
authors.initials: J
authors.lastname: Coimbra
authors.forename: Mauro
authors.initials: M
authors.lastname: Ravera
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gabano
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: António
authors.initials: A
authors.lastname: Paulo
mesh_terms: D000165:Acridine Orange / Q000737:chemistry; D000873:Anthracenes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D003959:Diamines / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D003959:Diamines; D008024:Ligands; D009944:Organoplatinum Compounds; D011720:Pyrazoles; D004247:DNA; C034020:anthracene; D000165:Acridine Orange