Synthesis and Biological Studies of Pyrazolyl‐Diamine PtII Complexes Containing Polyaromatic DNA‐Binding Groups
Identifieur interne : 001335 ( Main/Exploration ); précédent : 001334; suivant : 001336Synthesis and Biological Studies of Pyrazolyl‐Diamine PtII Complexes Containing Polyaromatic DNA‐Binding Groups
Auteurs : Sofia Gama [Portugal] ; Filipa Mendes [Portugal] ; Teresa Esteves [Portugal] ; Fernanda Marques [Portugal] ; Ant Nio Matos [Portugal] ; José Rino [Portugal] ; Joana Coimbra [Portugal] ; Mauro Ravera [Italie] ; Elisabetta Gabano [Italie] ; Isabel Santos [Portugal] ; Ant Nio Paulo [Portugal]Source :
- ChemBioChem [ 1439-4227 ] ; 2012-11-05.
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.
Platinum and intercalation: To achieve synergistic effects between intercalation and DNA platination, new pyrazolyl‐diamine PtII complexes containing anthracenyl (L2Pt) or acridine orange (L3Pt) groups were created, and their DNA interaction and cytotoxicity were investigated. L2Pt showed the highest cytotoxic potency, probably due to a different mode of action from those of L3Pt or cis‐DDP.
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DOI: 10.1002/cbic.201200472
Affiliations:
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de Anatomia Patológica</wicri:noRegion></affiliation></author><author><name sortKey="Rino, Jose" sort="Rino, Jose" uniqKey="Rino J" first="José" last="Rino">José Rino</name><affiliation wicri:level="1"><country xml:lang="fr">Portugal</country><wicri:regionArea>Faculdade de Medicina da Universidade de Lisboa–, Instituto Medicina Molecular, Av. 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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.</div><div type="abstract" xml:lang="en">Platinum and intercalation: To achieve synergistic effects between intercalation and DNA platination, new pyrazolyl‐diamine PtII complexes containing anthracenyl (L2Pt) or acridine orange (L3Pt) groups were created, and their DNA interaction and cytotoxicity were investigated. L2Pt showed the highest cytotoxic potency, probably due to a different mode of action from those of L3Pt or cis‐DDP.</div></front></TEI><affiliations><list><country><li>Italie</li><li>Portugal</li></country></list><tree><country name="Portugal"><noRegion><name sortKey="Gama, Sofia" sort="Gama, Sofia" uniqKey="Gama S" first="Sofia" last="Gama">Sofia Gama</name></noRegion><name sortKey="Coimbra, Joana" sort="Coimbra, Joana" uniqKey="Coimbra J" first="Joana" last="Coimbra">Joana Coimbra</name><name sortKey="Esteves, Teresa" sort="Esteves, Teresa" uniqKey="Esteves T" first="Teresa" last="Esteves">Teresa Esteves</name><name sortKey="Marques, Fernanda" sort="Marques, Fernanda" uniqKey="Marques F" first="Fernanda" last="Marques">Fernanda Marques</name><name sortKey="Matos, Ant Nio" sort="Matos, Ant Nio" uniqKey="Matos A" first="Ant Nio" last="Matos">Ant Nio Matos</name><name sortKey="Mendes, Filipa" sort="Mendes, Filipa" uniqKey="Mendes F" first="Filipa" last="Mendes">Filipa Mendes</name><name sortKey="Paulo, Ant Nio" sort="Paulo, Ant Nio" uniqKey="Paulo A" first="Ant Nio" last="Paulo">Ant Nio Paulo</name><name sortKey="Paulo, Ant Nio" sort="Paulo, Ant Nio" uniqKey="Paulo A" first="Ant Nio" last="Paulo">Ant Nio Paulo</name><name sortKey="Paulo, Ant Nio" sort="Paulo, Ant Nio" uniqKey="Paulo A" first="Ant Nio" last="Paulo">Ant Nio Paulo</name><name sortKey="Rino, Jose" sort="Rino, Jose" uniqKey="Rino J" first="José" last="Rino">José Rino</name><name sortKey="Santos, Isabel" sort="Santos, Isabel" uniqKey="Santos I" first="Isabel" last="Santos">Isabel Santos</name></country><country name="Italie"><noRegion><name sortKey="Ravera, Mauro" sort="Ravera, Mauro" uniqKey="Ravera M" first="Mauro" last="Ravera">Mauro Ravera</name></noRegion><name sortKey="Gabano, Elisabetta" sort="Gabano, Elisabetta" uniqKey="Gabano E" first="Elisabetta" last="Gabano">Elisabetta Gabano</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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