Cytotoxicity of half sandwich ruthenium(II) complexes with strong hydrogen bond acceptor ligands and their mechanism of action

Neutral and cationic organometallic ruthenium(II) piano stool complexes of the type [(eta(6)-cymene)R-uCl(X)(Y)] (complexes R1-R8) has been synthesized and characterized. In cationic complexes, X, Y is either a eta(2) phosphorus ligand such as 1,1-bis(diphenylphosphino)methane (DPPM) and 1,2-bis(diphenylphosphino)ethane (DPPE) or partially oxidized ligands such as 1,2-bis(diphenylphosphino)methane monooxide (DPPMO) and 1,2-bis(diphenylphosphino)ethane monooxide (DPPEO) which are strong hydrogen bond acceptors. In neutral complexes. X is chloride and Y is a monodentate phosphorous donor. Complexes with DPPM and DPPMO ligands ([(eta(6)-cymene)Ru(eta(2)-DPPM)Cl]PF6 (R2), [(eta(6)-cymene)Ru(eta(2)-DPPMO)Cl]PF6 (R3), [(eta(6)-cymene)Ru(eta(1)-DPPM)Cl-2] (R5) and [(eta(6)-cymene)Ru(eta(1)-DPPMO)Cl-2] (R6) show good cytotoxicity. Growth inhibition study of several human cancer cell lines by these complexes has been carried out. Mechanistic studies for R5 and R6 show that inhibition of cancer cell growth involves both cell cycle arrest and apoptosis induction. Using an apoptosis PCR array, we identified the sets of antiapoptotic genes that were down regulated and pro-apoptotic genes that were up regulated. These complexes were also found to be potent metastasis inhibitors as they prevented cell invasion through matrigel. The complexes were shown to bind DNA in a non intercalative fashion and cause unwinding of plasmid DNA in cell-free medium by competitive ethidium bromide binding, viscosity measurements, thermal denaturation and gel mobility shift assays.

Comparative Analyses of Age- and Sex-Specific Patterns of Vocal Behaviour in Four Species of Old World Monkeys

Sound recordings and behavioural data were collected from four primate species of two genera (Macaca, Presbytis). Comparative analyses of structural and behavioural aspects of vocal communication revealed a high degree of intrageneric similarity but striking intergeneric differences. In the two macaque species (Macaca silenus, Macaca radiata), males and females shared the major part of the repertoire. In contrast, in the two langurs (Presbytis johnii, Presbytis entellus), many calls were exclusive to adult males. Striking differences between both species groups occurred with respect to age-specific patterns of vocal behaviour. The diversity of vocal behaviour was assessed from the number of different calls used and the proportion of each call in relation to total vocal output for a given age/sex class. In Macaca, diversity decreases with the age of the vocalizer, whereas in Presbytis the age of the vocalizer and the diversity of vocal behaviour are positively correlated. A comparison of the data of the two genera does not suggest any causal relationship between group composition (e.g. multi-male vs. one-male group) and communication system. Within each genus, interspecific differences in vocal behaviour can be explained by differences in social behaviour (e.g. group cohesion, intergroup relation, mating behaviour) and functional disparities. Possible factors responsible for the pronounced intergeneric differences in vocal behaviour between Macaca and Presbytis are discussed.

Anticancer Activity of Hydrogen-Bond-Stabilized Half-Sandwich RuII Complexes with Heterocycles

Neutral half-sandwich organometallic ruthenium(II) complexes of the type (?6-cymene)RuCl2(L)] (H1H10), where L represents a heterocyclic ligand, have been synthesized and characterized spectroscopically. The structures of five complexes were also established by single-crystal X-ray diffraction confirming a piano-stool geometry with ?6 coordination of the arene ligand. Hydrogen bonding between the N?H group of the heterocycle and a chlorine atom attached to Ru stabilizes the metalligand interaction. Complexes coordinated to a mercaptobenzothiazole framework (H1) or mercaptobenzoxazole (H6) showed high cytotoxicity against several cancer cells but not against normal cells. In vitro studies have shown that the inhibition of cancer cell growth involves primarily G1-phase arrest as well as the generation of reactive oxygen species (ROS). The complexes are found to bind DNA in a non-intercalative fashion and cause unwinding of plasmid DNA in a cell-free medium. Surprisingly, the cytotoxic complexes H1 and H6 differ in their interaction with DNA, as observed by biophysical studies, they either cause a biphasic melting of the DNA or the inhibition of topoisomerase IIa activity, respectively. Substitution of the aromatic ring of the heterocycle or adding a second hydrogen-bond donor on the heterocycle reduces the cytotoxicity.

Quantifying Vocal Mimicry in the Greater Racket-Tailed Drongo: A Comparison of Automated Methods and Human Assessment

Objective identification and description of mimicked calls is a primary component of any study on avian vocal mimicry but few studies have adopted a quantitative approach. We used spectral feature representations commonly used in human speech analysis in combination with various distance metrics to distinguish between mimicked and non-mimicked calls of the greater racket-tailed drongo, Dicrurus paradiseus and cross-validated the results with human assessment of spectral similarity. We found that the automated method and human subjects performed similarly in terms of the overall number of correct matches of mimicked calls to putative model calls. However, the two methods also misclassified different subsets of calls and we achieved a maximum accuracy of ninety five per cent only when we combined the results of both the methods. This study is the first to use Mel-frequency Cepstral Coefficients and Relative Spectral Amplitude - filtered Linear Predictive Coding coefficients to quantify vocal mimicry. Our findings also suggest that in spite of several advances in automated methods of song analysis, corresponding cross-validation by humans remains essential.

Substitution-Modulated Anticancer Activity of Half-Sandwich Ruthenium(II) Complexes with Heterocyclic Ancillary Ligands

Ten new organometallic half-sandwich ruthenium complexes with heterocyclic ligands have been synthesized (H1-H10). The substituents on the ancillary heterocyclic ligands were varied to understand the effect of substitution on anticancer activity. The crystallographic characterization of five complexes confirms that they adopt three-legged piano-stool structures and are stabilized by intramolecular hydrogen bonding. Complexes H2 and H3 also exhibit halogen bonding in the solid state. In aqueous media, the complexes form dinuclear ruthenium species. Complex H1 with a noncytotoxic heterocycle, 6-fluoro-2-mercaptobenzothiazole, and complex H11 with the unsubstituted 2-mercaptobenzothiazole are the most active against A2780 and KB cell lines. The substitution of the H atoms on the ancillary ligand with Cl or Br atoms leads to a decrease in the anticancer activity. With the exception of fluorine-substituted H5, the complexes with mercaptobenzoxazole (H6-H9) are inactive against all of the tested cell lines. Ruthenium complexes with mercaptonaphthimidazole (H10) and mercaptobenzimidazole (H13) do not show any anticancer activity. The active complexes show a biphasic melting curve when incubated with calf thymus (CT) DNA. These complexes only inhibit thioredoxin reductase (TrxR) enzyme activity to a small extent. The substitution of hydrogen atoms with fluorine atoms in the aromatic heterocyclic ligands on organometallic half-sandwich ruthenium complexes has the most beneficial effect on their anticancer activity.

Non-uniform beams and stiff strings isospectral to axially loaded uniform beams and piano strings

In this paper, we derive analytical expressions for mass and stiffness functions of transversely vibrating clamped-clamped non-uniform beams under no axial loads, which are isospectral to a given uniform axially loaded beam. Examples of such axially loaded beams are beam columns (compressive axial load) and piano strings (tensile axial load). The Barcilon-Gottlieb transformation is invoked to transform the non-uniform beam equation into the axially loaded uniform beam equation. The coupled ODEs involved in this transformation are solved for two specific cases (pq (z) = k (0) and q = q (0)), and analytical solutions for mass and stiffness are obtained. Examples of beams having a rectangular cross section are shown as a practical application of the analysis. Some non-uniform beams are found whose frequencies are known exactly since uniform axially loaded beams with clamped ends have closed-form solutions. In addition, we show that the tension required in a stiff piano string with hinged ends can be adjusted by changing the mass and stiffness functions of a stiff string, retaining its natural frequencies.