Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation

Heavy metal compounds have toxic and medicinal potential through capacity to form strong specific bonds with macromolecules, and the interaction of platinum drugs at the major groove nitrogen atom of guanine bases primarily underlies their therapeutic activity. By crystallographic analysis of transition metal-and in particular platinum compound-DNA site selectivity in the nucleosome core, we establish that steric accessibility, which is controlled by specific structural parameters of the double helix, modulates initial guanine-metal bond formation. Moreover, DNA conformational features can be linked to both similarities and distinctions in platinum drug adduct formation between the naked and nucleosomal DNA states. Notably, structures that facilitate initial platinum-guanine bond formation can oppose cross-link generation, rationalizing the occurrence of long-lived therapeutically ineffective monofunctional adducts. These findings illuminate DNA structure-dependent reactivity and provide a novel framework for understanding metal-double helix interactions, which should facilitate the development of improved chromatin-targeting medicinal agent

Investigation of glycation products by THz time-domain spectroscopy

Glycation is the non-enzymatic reaction betwee

Research of effectiveness of natural and modified sorbents for wastewater treatment based on mica quartzite treatment waste

Results of a research of efficiency of sorbents on the basis of the waste of production and processing of micaceous quartzites (MQ), montmorillonite clays (MC) modified by humic connections (HC), received by extraction of waste brown coal are shown. Chemical composition of mica quartzite processing waste depending on the fraction size was previously investigated: element structure by method of the power-dispersive X-ray fluorescent analysis and mineral structure by method of X-ray phase analysis, for purpose of interrelation establishment between the structure of fraction and adsorptive properties of the received composite sorbents and also for the purpose of an exception as a part of MQ and, respectively, a sorbent of dangerous and toxic substances I-III of hazard classes. The efficiency of adsorption of the obtained sorbents was studied, an increase in sorption activity was found depending on composition of sorbent and method of modification (preliminary temperature processing and drawing on a surface of a sorbent of HC nano- and a microdimensional layer). It is determined that the greatest efficiency of adsorption of ions of heavy metals is observed for the sorbent which underwent temperature modification at 800о C and then HC covered with a layer up to 1% of masses. Use of waste of MQ containing 40–60% of quartz (SiO2) in composition with MC and with further modification of a surface (up to 1% of masses.) humic connections will allow receiving highly effective, universal and inexpensive sorbents for sewage treatment from heavy metals and other pollutants. The offered composite sorbents will allow to solve several ecologically important problems in a complex: to carry out effective purification of industrial sewage (machine and instrument-making, metallurgical, petrochemical and other enterprises) of heavy metals ions and to utilize waste of micaceous quartz processing of and brown coal extraction

Influence of the Arene Ligand, the Number and Type of Metal Centers, and the Leaving Group on the in Vitro Antitumor Activity of Polynuclear Organometallic Compounds

Dinuclear ruthenium complexes were shown to exhibit strong antiproliferative properties in human tumor cell lines. In order to extend the structure−activity relationships (SARs), a series of new RuII(arene)X complexes (X = Cl, Br, I) linked by pyridinone-based spacers were synthesized and assayed for their in vitro antineoplastic effect. The SARs were established in terms of the arene ligand, the leaving group (the halide ligand), and the nature and number of the metal centers. It was demonstrated that, besides the previously shown effect of the spacer length, the nature of the metal center has the biggest influence on the in vitro anticancer activity. The halide ligand had no effect on the cytotoxicity, due to rapid formation of the same aquation product for all evaluated compounds. Furthermore, nearly identical activity was observed when varying the arene ligand from p-cymene to biphenyl. However, the number of metal centers was found to be important, with the dinuclear compound being more active than the analogous mono- and trinuclear species

Protein ruthenation and DNA alkylation: chlorambucil-functionalized RAPTA complexes and their anticancer activity

Chemotherapeutics for the treatment of tumorigenic conditions that feature novel modes of action are highly sought after to overcome the limitations of current chemotherapies. Herein, we report the conjugation of the alkylating agent chlorambucil to the RAPTA scaffold, a well-established pharmacophore. While chlorambucil is known to alkylate DNA, the RAPTA complexes are known to coordinate to amino acid side chains of proteins. Therefore, such a molecule combines DNA and protein targeting properties in a single molecule. Several chlorambucil-tethered RAPTA derivatives were prepared and tested for their cytotoxicity, stability in water and reactivity to protein and DNA substrates. The anticancer activity of the complexes is widely driven by the cytotoxicity of the chlorambucil moiety. However, especially in the cis-platin-resistant A2780R cells, the chlorambucil-functionalized RAPTA derivatives are in general more cytotoxic than chlorambucil and also a mixture of chlorambucil and the parent organoruthenium RAPTA compound. In a proof-of-principle experiment, the cross-linking of DNA and protein fragments by a chlorambucil-RAPTA derivative was observed

Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation

Heavy metal compounds have toxic and medicinal potential through capacity to form strong specific bonds with macromolecules, and the interaction of platinum drugs at the major groove nitrogen atom of guanine bases primarily underlies their therapeutic activity. By crystallographic analysis of transition metal–and in particular platinum compound–DNA site selectivity in the nucleosome core, we establish that steric accessibility, which is controlled by specific structural parameters of the double helix, modulates initial guanine–metal bond formation. Moreover, DNA conformational features can be linked to both similarities and distinctions in platinum drug adduct formation between the naked and nucleosomal DNA states. Notably, structures that facilitate initial platinum–guanine bond formation can oppose cross-link generation, rationalizing the occurrence of long-lived therapeutically ineffective monofunctional adducts. These findings illuminate DNA structure-dependent reactivity and provide a novel framework for understanding metal–double helix interactions, which should facilitate the development of improved chromatin-targeting medicinal agents