DNA-binding preferences of bisantrene analogues: relevance to the sequence specificity of drug-mediated topoisomerase II poisoning

To elucidate structure-activity relationships for drugs that are able to poison or inhibit topoisomerase II, we investigated the thermodynamics and stereochemistry of the DNA binding of a number of anthracene derivatives bearing one or two 4, 5-dihydro-1H-imidazol-2-yl-hydrazone side chains (characteristic of bisantrene) at different positions of the planar aromatic system. An aza-bioisostere, which can be considered a bisantrene-amsacrine hybrid, was also tested. The affinity for nucleic acids in different sequence contexts was evaluated by spectroscopic techniques, using various experimental conditions. DNA-melting and DNase I footprinting experiments were also performed. The location and number of the otherwise identical side chains dramatically affected the affinity of the test compounds for the nucleic acid. In addition, the new compounds exhibited different DNA sequence preferences, depending on the locations of the dihydroimidazolyl-hydrazone groups, which indicates a major role for the side-chain position in generating specific contacts with the nucleic acid. Molecular modeling studies of the intercalative binding of the 1- or 9-substituted isomers to DNA fully supported the experimental data, because a substantially more favorable recognition of A-T steps, compared with G-C steps, was found for the 9-substituted derivative, whereas a much closer energy balance was found for the 1-substituted isomer. These results compare well with the alteration of base specificity found for the topoisomerase II-mediated DNA cleavage stimulated by the isomeric drugs. Therefore, DNA-binding specificity appears to represent an important determinant for the recognition of the topoisomerase-DNA cleavable complex by the drug, at least for poisons belonging to the amsacrine-bisantrene family.     

The effect of cooking on Brassica vegetables

Assessing antioxidant intake requires a food antioxidant database. However, cooking may affect antioxidant content due to antioxidant release, destruction or creation of redox-active metabolites. Here, effects of boiling, steaming and microwaving of broccoli, cauliflower, cabbage and choy-sum (Chinese cabbage) were explored by measuring antioxidant contents of raw and cooked vegetables. Cooking water was also tested. For all cooked vegetables, antioxidant content was highest in steamed > boiled > microwaved, and decreased with longer cooking time, regardless of method. All steamed vegetables had higher antioxidant contents than had matching raw vegetables. Effects were variable for boiling and microwaving. Microwaving caused greater antioxidant loss into cooking water than did boiling. Marked losses of anitoxidants occurred in microwaved cabbage and spinach. To assess food antioxidant content/intake accurately, cooking effects need detailed study. Steaming may be the cooking method of choice to release/conserve antioxidants. The cooking water is a potentially rich source of dietary antioxidants.     

EMC整装出击

2010年5月，EMC把旗下负责内容归档和管理的部门（原软件事业部）重新整合，并命名为信息智能事业部（IIG），这项在外人眼中小小的部门调整背后实际上蕴含了EMC进军软件服务行业的雄心。     

Modeling and biological investigations of an unusual behavior of novel synthesized acridine-based polyamine ligands in the binding of double helix and G-quadruplex DNA

Three novel 2,7-substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double-stranded and G-quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open-chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m-AMSA, efficiently intercalating into dsDNA, but stabilizing G-quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient π-π and H-bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G-quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G-quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2>L3>L1) toward G-quadruplex that was observed in this study.     

只拍MM的Sissi MM

山水：最早认识Sissi是在一个IT技术论坛CU上，她拍摄的MM作品风格清新，纯情，给我印象很深。傻傻的，Sissi（网名叫玉米）从一个IT圈的摄影发烧友，开始步入商业摄影（这已经是我认识的N个IT圈摄友的类似经历了）。     

Amino-Acid-Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G-Quadruplexes

Guanine-rich sequences are known to fold into G-quadruplex (G4) arrangements, which are present in oncogenes and in the telomeric regions of chromosomes. In particular, G4s represent an obstacle to functioning of telomerase, an enzyme overexpressed in cancer cells causing their immortalization. Therefore, G4 stabilization using small molecules represents an appealing strategy for the medicinal chemist. Ligands based on an anthraquinone scaffold, to which peptidic side chains were attached by an amide bond, were previously reported. We envisioned improving this ligand concept leveraging the click chemistry approach, which, besides representing a flexible, high yielding synthetic strategy, allows an elongation of the side chains and an increase of π–π stacking and H-bond interactions with the nucleobases through the triazole ring. Compounds were tested for their ability to interact with G4 DNA with a multiple analytical approach, demonstrating an elevated aptitude to stabilize the G4 and high selectivity over double stranded DNA.     

Mg(2+)-mediated binding of 6-substituted quinolones to DNA: relevance to biological activity

The interaction of a number of novel 6-substituted quinolone derivatives with DNA in the presence/absence of magnesium ions has been investigated by fluorometric techniques. The drug-single-stranded nucleic acid interaction is invariantly mediated by the metal ion. In all cases optimal complex formation is found at physiological Mg2+ concentration. From titrations at different [Mg2+] the binding constant for the ternary drug-DNA-Mg2+ complex (KT) has been evaluated. Interestingly, a good relationship is found between KT and gyrase poisoning activity of the test quinolones (IC50), which confirms that DNA-affinity of the quinolone, modulated by Mg2+, plays an important role in poisoning the cleavable gyrase-DNA complex and, consequently, in eliciting antibacterial activity in this family of drugs. The results obtained with different 6-substituted compounds supports the idea that position 6 of the drug, besides playing a pharmacokinetic role, is involved in recognition of the enzyme pocket. Our data do not support a mechanism of action based upon quinolone intercalation into B-DNA.     

Capillarity-driven dynamics of water–alcohol mixtures in nanofluidic channels

We investigated the spontaneous capillarity-driven filling of nanofluidic channels with a thickness of 6 and 16 nm using mixtures of ethanol and water of variable composition. To improve the visibility of the fluid, we embedded metal mirrors into the top and bottom walls of the channels that act as a Fabry–Pérot interferometer. The motion of propagating liquid–air menisci was monitored for various concentrations in transmission with an optical microscope. In spite of the visible effects of surface roughness and different affinity of water and ethanol to the channel walls, the dynamics followed the classical t ^1/2—dependence according to Lucas and Washburn. While the prefactor of this algebraic relation falls short of the expectations based on bulk properties by 10–30%, the relative variation between mixtures of different composition follows the expectations based on the bulk surface tension and viscosity, implying that—despite the small width of the channels and the large surface-to-volume ratio—specific adsorption or chemical selectivity effects are not relevant. We briefly discuss the impact of surface roughness on our experimental results.     

Rational Design,Synthesis, Biophysical and Antiproliferative Evaluation of Fluorenone Derivatives with DNA G‐Quadruplex Binding Properties

Molecular modeling studies carried out with experimental DNA models with the sequence d[AG₃(T₂AG₃)₃] suggest that the introduction of a net positive charge onto the side chain of a series of fluorenone carboxamides can improve G‐quadruplex binding. The terminal morpholino moiety was replaced with a novel N‐methylmorpholinium cation starting from two 4‐carboxamide compounds. A different substitution on the fluorenone ring was also investigated and submitted to the same quaternarization process. All compounds were analyzed for their DNA binding properties by competition dialysis methods. In vitro antiproliferative tests were carried out against two different tumor cell lines. Docking experiments were conducted by including all four known human repeat unit G‐quadruplex DNA sequences (27 experimentally determined conformations) against the most active fluorenone derivatives. The results of theoretical, biophysical, and in vitro experiments indicate two novel derivatives as lead compounds for the development of a new generation of G‐quadruplex ligands with greater potency and selectivity.     

DNA reactivity profile of trans-platinum planar amine derivatives

New trans-platinum planar amines (TPAs) represent a family of platinum-based drugs with cytotoxicity equivalent to that of cisplatin, but with negligible cross-resistance. According to the substitution pattern around the metal center, distinct DNA adducts can be formed which yield various levels of cytotoxicity in cell lines. We compared the effects of leaving groups (Cl(-) versus formate or acetate) and amines (NH(3) versus aromatic heterocyclic planar systems) on the efficiency, kinetics, and mode of DNA platination. We show that the substitution of just a single amino group on the transplatin nucleus is optimal, with major effects on the kinetics of metal complex conversion into the reactive aquo species. Additionally, by monitoring TPA reactivity toward variable DNA structures, a lack of preference for double-stranded DNA in over single-stranded or G-quadruplex DNA was observed which is possibly related to steric effects of the planar amine groups. These properties can lead to a unique distribution of platination sites by TPA relative to the lead compound cisplatin, which may help to explain the unique cytotoxic profile of TPAs.