DNA Interactions of Monofunctional Organometallic Ruthenium(II) Antitumor Complexes in Cell-free Media

Modifications of natural DNA in a cell-free medium by antitumor monodentate Ru(II) arene compounds of the general formula [(eta 6-arene)Ru(en)Cl]+ (arene ) biphenyl, dihydroanthracene, tetrahydroanthracene, p-cymene, or benzene; en ) ethylenediamine) were studied by atomic absorption, melting behavior, transcription mapping, circular and linear dichroism, plasmid unwinding, competitive ethidium displacement, and differential pulse polarography. The results indicate that these complexes bind preferentially to guanine residues in double-helical DNA. The data are consistent with DNA binding of the complexes containing biphenyl, dihydroanthracene, or tetrahydroanthracene ligands that involves combined coordination to G N7 and noncovalent, hydrophobic interactions between the arene ligand and DNA, which may include arene intercalation and minor groove binding. In contrast, the single hydrocarbon rings in the p-cymene and benzene ruthenium complexes cannot interact with double-helical DNA by intercalation. Interestingly, the adducts of the complex containing p-cymene ligand, which has methyl and isopropyl substituents, distort the conformation and thermally destabilize double-helical DNA distinctly more than the adducts of the three multiring ruthenium arene compounds. It has been suggested that the different character of conformational alterations induced in DNA, and the resulting thermal destabilization, may affect differently further “downstream” effects of damaged DNA and consequently may result in different biological effects of this new class of metal-based antitumor compounds. The results point to a unique profile of DNA binding for Ru(II) arene compounds, suggesting that a search for new anticancer compounds based on this class of complexes may also lead to an altered profile of biological activity in comparison with that of metal-based antitumor drugs already used in the clinic or currently on clinical trials

Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat

Orphanin FQ (OFQ) is the endogenous agonist of the opioid receptor-like receptor (ORL-1). It and its precursor, prepro-OFQ, exhibit structural features suggestive of the opioid peptides. A cDNA encoding the OFQ precursor sequence in the rat recently has been cloned, and the authors recently generated a polyclonal antibody directed against the OFQ peptide. In the present study, the authors used in situ hybridization and immunohistochemistry to examine the distribution of OFQ peptide and mRNA in the central nervous system of the adult rat. OFQ immunoreactivity and prepro-OFQ mRNA expression correlated virtually in all brain areas studied. In the forebrain, OFQ peptide and mRNA were prominent in the neocortex endopiriform nucleus, claustrum, lateral septum, ventral forebrain, hypothalamus, mammillary bodies, central and medial nuclei of the amygdala, hippocampal formation, paratenial and reticular nuclei of the thalamus, medial habenula, and zona incerta. No OFQ was observed in the pineal or pituitary glands. In the brainstem, OFQ was prominent in the ventral tegmental area, substantia nigra, nucleus of the posterior commissure, central gray, nucleus of Darkschewitsch, peripeduncular nucleus, interpeduncular nucleus, tegmental nuclei, locus coeruleus, raphe complex, lateral parabrachial nucleus, inferior olivary complex, vestibular nuclear complex, prepositus hypoglossus, solitary nucleus, nucleus ambiguous, caudal spinal trigeminal nucleus, and reticular formation. In the spinal cord, OFQ was observed throughout the dorsal and ventral horns. The wide distribution of this peptide provides support for its role in a multitude of functions, including not only nociception but also motor and balance control, special sensory processing, and various autonomic and physiologic processes. J. Comp. Neurol. 406:503–547, 1999. © 1999 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34452/1/7_ftp.pd

Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)]

The photocytotoxicity and photobiochemical properties of the new complex trans, trans, trans-[Pt(N3)2(OH)2(NH3)(piperidine)] (5) are compared with its analogue containing the less basic and less lipophilic ligand pyridine (4). The log P (n-octanol/water) values were of -1.16 and -1.84 for the piperidine and pyridine complexes, respectively, confirmed that piperidine increases the hydrophobicity of the complex. DFT and TDDFT calculations indicate that 5 has accessible singlet and triplet states which can promote ligand dissociation when populated by both UVA and visible white light. When activated by UVA or white light, both compounds showed similar cytotoxic potencies in various human cancer cell lines although their selectivity was different. The time needed to reach similar antiproliferative activity was noticeably decreased by introducing the piperidine ligand. Neither compound showed cross-resistance in three oxoplatin-resistant cell lines. Furthermore, both compounds showed similar anticlonogenic activity when activated by UVA radiation. Interactions of the light-activated complexes with DNA showed similar kinetics and levels of DNA platination and similar levels of DNA interstrand cross-linking (ca. 5 %). Also the ability to unwind double stranded DNA where comparable for the piperidine analogue (24°, respectively), while the piperidine complex showed higher potency in changing the conformation of DNA, as measured in an ethidium bromide binding assay. These results indicate that the nature of the heterocyclic nitrogen ligand can have subtle influences on both the phototoxicity and photobiochemistry of this class of photochemotherapeutic agents

Reconstitution en trois dimensions d'un sol d'habitat préhistorique : Exemple de la Caune de l'Arago (Tautavel, Pyrénées-Orientales, France)

International audienceThe Caune de l'Arago is a site from the Middle Pleistocene witch has been the subject of excavations for more than thirty-five years. Those excavations have given place to many analysis. The results of these various studies have been seized in the database "Prehistoric and Paleontologic Material" or have been scanned to constitute a numerical library. The important development of informatic tools enables to undertake the three-dimensional reconstruction of prehistoric ground of settlement and to enter upon the simulation of the geodynamic evolution of the quaternary filling of the Caune de l'Arago.La Caune de l'Arago est un site du Pléistocène moyen qui à déjà fait l'objet de plus de trente cinq années de fouilles qui ont donné lieu à de nombreuses analyses. Les résultats de ces diverses études ont été saisis dans la Base de Données "Matériel Paléontologique et Préhistorique" ou scannérisés pour constituer une bibliothèque numérique. L'important développement de l'outil informatique permet d'entreprendre la reconstitution en trois dimensions d'un sol d'habitat préhistorique et d'aborder la simulation de l'évolution géodynamique des dépôts quaternaires de la Caune de l'Arago

Reconstitution en trois dimensions d'un sol d'habitat préhistorique : Exemple de la Caune de l'Arago (Tautavel, Pyrénées-Orientales, France)

International audienceThe Caune de l'Arago is a site from the Middle Pleistocene witch has been the subject of excavations for more than thirty-five years. Those excavations have given place to many analysis. The results of these various studies have been seized in the database "Prehistoric and Paleontologic Material" or have been scanned to constitute a numerical library. The important development of informatic tools enables to undertake the three-dimensional reconstruction of prehistoric ground of settlement and to enter upon the simulation of the geodynamic evolution of the quaternary filling of the Caune de l'Arago.La Caune de l'Arago est un site du Pléistocène moyen qui à déjà fait l'objet de plus de trente cinq années de fouilles qui ont donné lieu à de nombreuses analyses. Les résultats de ces diverses études ont été saisis dans la Base de Données "Matériel Paléontologique et Préhistorique" ou scannérisés pour constituer une bibliothèque numérique. L'important développement de l'outil informatique permet d'entreprendre la reconstitution en trois dimensions d'un sol d'habitat préhistorique et d'aborder la simulation de l'évolution géodynamique des dépôts quaternaires de la Caune de l'Arago