Synthesis and Biological Studies of Pyrazolyl‐Diamine PtII Complexes Containing Polyaromatic DNA‐Binding Groups |
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Authors: | Dr. Sofia Gama Dr. Filipa Mendes Dr. Teresa Esteves Dr. Fernanda Marques Dr. António Matos Dr. José Rino Dr. Joana Coimbra Dr. Mauro Ravera Dr. Elisabetta Gabano Dr. Isabel Santos Dr. António Paulo |
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Affiliation: | 1. Instituto Superior Técnico, Instituto Tecnológico e Nuclear, Unidade de Ciências Químicas e Radiofarmacêuticas, Estrada Nacional 10, 2686‐953 Sacavém (Portugal);2. Centro Hospitalar de Lisboa Central Hospital Curry Cabral, Servi?o de Anatomia Patológica, R. da Beneficência 8 1069‐166 Lisboa (Portugal);3. Faculdade de Medicina da Universidade de Lisboa–, Instituto Medicina Molecular, Av. Prof. Egas Moniz, 1649‐028 Lisboa (Portugal);4. Universidade de Aveiro, Laboratório Central de Análises, Campo de Santiago 3810–193 Aveiro Campus de Santiago, Aveiro (Portugal);5. Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale “Amedeo Avogadro”, Viale Michel 11, 15100, Alessandria (Italy) |
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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 L2Pt displays a covalent type of binding, whereas the acridine orange counterpart L3Pt shows a combination of intercalative and covalent binding modes with a strong contribution from the former. L2Pt 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, L2Pt is nine to 27 times more cytotoxic than cisplatin. In the sensitive cell line, L3Pt showed a cytotoxic activity similar to that of cisplatin, but like L2Pt was able significantly to overcome cisplatin cross‐resistance. Cell‐uptake studies showed that L2Pt accumulates preferentially in the cytoplasm, whereas L3Pt 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 L2Pt because this compound, despite having a weaker ability to target the cell nucleus than L3Pt , as well as an inferior DNA affinity, is nevertheless more cytotoxic. Furthermore, ultrastructural studies of A2870 cells exposed to L2Pt and L3Pt revealed that these complexes induce different alterations in cell morphology, thus indicating the involvement of different modes of action in cell death. |
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Keywords: | antitumor agents cytotoxicity DNA binding platinum complexes pyrazolyl ligands |
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