Síntesis, caracterización y estudios de hidrólisis de complejos trans-[PtCl2(15N-amina)(15N-amina')] por RMN 2D [1H,15N] HSQC: citotoxicidad y fotoquímica de complejos de PtII y PtIV

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Inorgánica. Fecha de lectura: 19-12-200

Synthesis, reactivity studies, and cytotoxicity of two trans-Iodidoplatinum(II) complexes. Does photoactivation work?

trans-Platinum complexes have been the landmark in unconventional drugs prompting the development of innovative structures that might exhibit chemical and biological profiles different to cisplatin. Iodido complexes signaled a new turning point in the platinum drug design field when their cytotoxicity was reevaluated and reported. In this new study, we have synthesized and evaluated diodidoplatinum complexes trans-[PtI2(amine)(pyridine)] bearing aliphatic amines (isopropylamine and methylamine) and pyridines in trans configuration. X-ray diffraction data support the structural characterization. Their cytotoxicity has been evaluated in tumor cell lines such as SAOS-2, A375, T-47D, and HCT116. Moreover, we report their solution behavior and reactivity with biological models. Ultraviolet-a (UVA) irradiation induces an increase in their reactivity towards model nucleobase 5′-GMP in early stages, and promotes the release of the pyridine ligand (spectator ligand) at longer reaction times. Density Functional calculations have been performed and the results are compared with our previous studies with other iodido derivatives.MINECO CTQ-2015-68779

Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides

We show that UVA irradiation (365 nm) of the Pt-IV complex trans,trans,trans-[(PtCl2)-Cl-IV(OH)(2)(dimethylamine) (isopropylamine)] (1), induces reduction to Pt-II photoproducts. For the mixed amine Pt-II complex, trans[(PtCl2)-Cl-II(isopropylamine)(methylamine)] (2), irradiation at 365 nm increases the rate and extent of hydrolysis, triggering the formation of diaqua species. Additionally, irradiation increases the extent of reaction of complex 2 with guanosine-5'-monophosphate and affords mainly the bis-adduct, while reactions with adenosine-5'-monophosphate and cytidine-5'-monophosphate give rise only to mono-nucleotide adducts. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 1 and 2, and their photophysical and photochemical properties. UVA-irradiation can contribute to enhanced cytotoxic effects of diamine platinum drugs with trans geometry

Trans platinum complexes design: One novel water soluble oxime derivative that contains aliphatic amines in trans configuration

7 páginas, 5 figuras, 1 tabla -- PAGS nros. 104-110In an attempt to design new antitumoral drugs based on transplatin complexes, we determined the experimental conditions for the preparation of trans-[Pt((CH3)2CNOH)((CH3)2CHNH2)Cl2], and solved the crystal structure. The cytotoxicity of the novel complex, the cis counterpart, cisplatin, and a trans complex with aliphatic amines, as well as the capacity of some of these complexes to cause either apoptotic or necrotic cell death, was comparatively examined in NRK-52E rat renal tubular cells and HepG2 human hepatoma cells. The results indicate that the oxime complex with trans geometry, but not the one with cis geometry, causes death by apoptosis, making the complex potentially suitable for therapeutic purposes. However cytotoxicity values are higher in the case of cis geometry than in trans geometry in both tumoral and non-tumoral cell linesAuthors thank the Spanish Ministry of Science and Education, Spanish CICYT Grants: SAF2003-01700 and SAF2004-01250Peer reviewe

Assembly of Palladium(II) and Platinum(II) Metallo-Rectangles with a Guanosine-Substituted Terpyridine and Study of Their Interactions with Quadruplex DNA

International audienceTwo novel [2+2] metallo-assemblies based on a guanosine-substituted terpyridine ligand (1) coordinated to palladium(II) (2a) and platinum(II) (2b) are reported. These supramolecular assemblies have been fully characterized by NMR spectroscopy, ESI mass spectrometry and elemental analyses. The palladium(II) complex (2a) has also been characterized by single crystal X-ray diffraction studies confirming that the system is a [2+2] metallo-rectangle in the solid state. The stabilities of these [2+2] assemblies in solution have been confirmed by DOSY studies as well as by variable temperature 1H NMR spectroscopy. The ability of these di-nuclear complexes to interact with quadruplex and duplex DNA was investigated by Fluorescent Intercalator Displacement (FID) assays, Fluorescence Resonance Energy Transfer (FRET) meting studies, and electrospray mass spectrometry (ESI-MS). These studies have shown that both these assemblies interact selectively with quadruplex DNA (human telomeric DNA and the G-rich promoter region of c-Myc oncogene) over duplex DNA, and are able to induce dimerization of parallel G-quadruplex structures

Back Cover: Quadruplex DNAâ Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers (Chem. Eur. J. 7/2016)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137289/1/chem201600136.pd

The preparation and characterization of trans-platinum(IV) complexes with unusually high cytotoxicity

4 páginas, 2 figuras, 3 tablas.The physical and biological properties have been determined for three Pt(IV) complexes with trans amine ligands: trans,trans,trans-[PtCl2(OH)2(dimethylamine)(isopropylamine)] (1IV), trans,trans,trans-[PtCl2(OH)2(dimethylamine)(methylamine)] (2IV) and trans,trans,trans-[PtCl2(OH)2(isopropylamine)(methylamine)] (3IV). The crystal structures of 2IV and 3IV reveal substantial strain resulting from repulsion between the amine ligands and the chlorido and hydroxido ligands. All three complexes have reduction potentials in the range −666 to −770 mV, values usually associated with high resistance to reduction and low cytotoxicity. However, the complexes all demonstrate surprisingly high cytotoxicity with values and trends that closely follow those seen for the Pt(II) congeners of these complexes. These results are consistent with more rapid reduction of the Pt(IV) complexes than would be expected based on the reduction potentials, perhaps associated with the trans arrangement of the chlorido ligands.We would like to thank the International cooperation program: COST D39 action for financial support. CNR, AGQ and LC thank the Spanish Comision Interministerial de Ciencia y Tecnología (CICYT-SAF-2009-09431) and Universidad Autónoma de Madrid for funding.Peer reviewe

The second generation of iodido complexes: Trans-[PtI2(amine) (amine′)] bearing different aliphatic amines

The antitumoral potential for a series of platinum iodido complexes, all bearing the same aliphatic amines (first iodido complexes generation), was demonstrated in a previous study. Concretely, cis complexes were shown to have a peculiar and different reactivity compared to cisplatin with sulfur donors models and Cyt C. In this work we have synthesized and studied iodido complexes bearing different aliphatic amines in trans configuration (the second generation) to investigate their potential antitumor activity in a panel of cell lines. Their interaction with biological models such as pBR322 and smaller biomolecules (5′-GMP, 9EtG, N-AcMet and N-AcCys) have been studied and compared to cisplatin and to the first iodido series. Their cytotoxicity, on the other hand, turned out to be especially active towards cell lines where cisplatin has no effect. © 2013 Elsevier Inc.Authors would like to thank the Spanish Ministry of Science and Education, Spanish CICYT Grants: SAF-2009-09431 and SAF2012-34424.Peer Reviewe

Quadruplex DNA-stabilising dinuclear platinum(II) terpyridine complexes with flexible linkers

Four dinuclear terpyridineplatinum(II) (Pt–terpy) complexes were investigated for interactions with G-quadruplex DNA (QDNA) and duplex DNA (dsDNA) by synchrotron radiation circular dichroism (SRCD), fluorescent intercalator displacement (FID) assays and fluorescence resonance energy transfer (FRET) melting studies. Additionally, computational docking studies were undertaken to provide insight into potential binding modes for these complexes. The complexes demonstrated the ability to increase the melting temperature of various QDNA motifs by up to 17 °C and maintain this in up to a 600-fold excess of dsDNA. This study demonstrates that dinuclear Pt–terpy complexes stabilise QDNA and have a high degree of selectivity for QDNA over dsDNA