Ruthenium polypyridyl complexes and their modes of interaction with DNA: is there a correlation between these interactions and the antitumor activity of the compounds?

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy)L(1)L(2)]((2-n)+), and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}(2){mu-H(2)N(CH(2))(6)NH(2)}](4+). The ligand tpy is 2,2':6',2''-terpyridine and the ligand L(1) is a bidentate ligand, namely, apy (2,2'-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L(2) is a labile monodentate ligand, being Cl(-), H(2)O, or CH(3)CN. All six species containing a labile L(2) were found to be able to coordinate to the DNA model base 9-ethylguanine by (1)H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure-activity relationships that might be used to guide optimization of the activity of agents of this class of compounds.

Interaction between the DNA model base 9-ethylguanine and a group of ruthenium polypyridyl complexes: kinetics and conformational temperature dependence.

The binding capability of three ruthenium polypyridyl compounds of structural formula [Ru(apy)(tpy)Ln-](ClO4)(2-n) [1a-c; apy = 2,2'-azobis(pyridine), tpy = 2,2':6',2''-terpyridine, L = Cl, H2O, CH3CN] to a fragment of DNA was studied. The interaction between each of these complexes and the DNA model base 9-ethylguanine (9-EtGua) was followed by means of 1H NMR studies. Density functional theory calculations were carried out to explore the preferential ways of coordination between the ruthenium complexes and guanine. The ruthenium-9-EtGua adduct formed was isolated and fully characterized using different techniques. A variable-temperature 1H NMR experiment was carried out that showed that while the 9-EtGua fragment was rotating fast at high temperature, a loss of symmetry was suffered by the model base adduct as the temperature was lowered, indicating restricted rotation of the guanine residue.

Posture-induced changes in intracranial pressure: a comparative study in patients with and without a cerebrospinal fluid block at the craniovertebral junction.

OBJECTIVE: The aim of this study was to determine posture-induced changes in intracranial pressure (ICP) when patients with hydrocephalus or idiopathic intracranial hypertension remained supine for 1 hour and then sat up and remained sitting for 3 hours. METHODS: Continuous ICP was monitored using a fiberoptic extradural sensor in: 1) 259 patients with hydrocephalus or idiopathic intracranial hypertension with free cerebrospinal fluid (CSF) flow through the craniovertebral junction and Sylvian aqueduct, 2) 20 patients with hydrocephalus secondary to aqueductal stenosis with free CSF flow through the craniovertebral junction, and 3) 97 patients with hydrocephalus associated with Chiari malformation. The maximum ICP difference (DeltaICP) was calculated as the difference between mean ICP in the supine position and minimum ICP value after changing body position. The mean ICP difference (DeltaICPmean) was calculated as the difference between the mean ICP in the supine position and the mean ICP while the patient was in a sitting position. RESULTS: In the complete sample, the median of DeltaICP was 13 mm Hg (interquartile range 10-17). The median of DeltaICPmean was 8 mm Hg (interquartile range 5-11). Both DeltaICP and DeltaICPmean were significantly greater in patients without obstruction in the craniospinal junction than in those with Chiari malformation (P = 0.005 and P = 0.014, respectively). No differences were found in DeltaICP or DeltaICPmean between patients with Sylvian aqueduct stenosis and those without (P = 0.777 and P = 0.346, respectively). CONCLUSION: ICP reduction after a change in body position is significantly greater in patients with free CSF flow through the craniospinal junction than in those with Chiari malformation, indicating the difficulty or impossibility of CSF displacement into the spinal canal in the latter.