Novel platinum(II)-based anticancer complexes and molecular hosts as their drug delivery vehicles

Platinum(II)-based DNA intercalators where the intercalating ligand is 1,10-phenanthroline or a phenanthroline derivative and where the ancillary ligand is either achiral (e.g. ethylenediamine) or chiral (e.g. diaminocyclohexane) show a range of cytotoxicities with a defined structure-activity relationship. The most cytotoxic are those that contain methylated-phenanthroline ligands and 1S,2S-diaminocyclohexane (S,S-dach) as the ancillary ligand. We have developed a new purification method using Sep-Pak C-18 reverse phase columns, which means these metal complexes can be made faster and cheaper compared to published methods. Platinum(II)-based complexes containing imidazole, pyrrole and beta-alanine subunits, that are capable of recognising specific DNA base-pair sequences have also been synthesised. These include linear or hairpin polyamide ligands that can recognise DNA sequences up to seven base-pairs in length and contain single platinum centres capable of forming monofunctional adducts with DNA. We have now synthesised and characterised, by (1)H and (195)Pt NMR, ESI-MS and elemental analysis, the first dinuclear platinum(II) DNA sequence selective agent. Finally, using (1)H NMR we have examined the encapsulation of our platinum(II)-based DNA intercalators by cucurbit[6]uril (CB[6]). Encapsulation by CB[6] was found to not significantly change the cytotoxicity of five platinum(II)-based DNA intercalators, indicating it may have utility as a molecular carrier for improved drug delivery.     

金属氧化物与现代微电子学:过渡金属前体化合物及转化为材料的化学过程

金属氧化物薄膜如HfO₂（被称为高k电介质）是现代微电子器件的关键组件,广泛用于计算机（平板电脑,笔记本电脑和台式机）、智能电话、智能电视、汽车和医疗设备中。具有大介电常数（k）的金属氧化物已经取代了介电常数小的SiO₂（k=3.9）,从而使得微电子元件进一步小型化。过渡金属化合物在化学气相沉积（CVD）和原子层沉积（ALD）中被广泛用作前体,通过与O₂、H₂O或O₃的反应生成金属氧化物薄膜。微电子金属氧化物膜是纳米材料最广泛应用的一个领域。本文概观该领域的最新进展,包括我们对d⁰过渡金属配合物与O₂反应的研究。     

Kinetics of Electrophilic Fluorination of Steroids and Epimerisation of Fluorosteroids

Fluorinated steroids, which are synthesised by electrophilic fluorination, form a significant proportion of marketed pharmaceuticals. To gain quantitative information on fluorination at the 6-position of steroids, kinetics studies were conducted on enol ester derivatives of progesterone, testosterone, cholestenone and hydrocortisone with a series of electrophilic N−F reagents. The stereoselectivities of fluorination reactions of progesterone enol acetate and the kinetic effects of additives, including methanol and water, were investigated. The kinetics of epimerisation of 6β-fluoroprogesterone to the more pharmacologically active 6α-fluoroprogesterone isomer in HCl/acetic acid solutions are detailed.     

Comparison of a high‐performance liquid chromatography method for quantification of carbamazepine with chemiluminescent microparticle immunoassay

Carbamazepine is an antiepileptic drug widely used for the treatment of epilepsy. In the National Institute of Neurology, monitoring has been performed using the technique chemiluminescent microparticle immunoassay (CMIA) in an automated way during the last five years. The aim of this study was to develop a simple and rapid HPLC analytical method coupled to DAD‐UV detection for the determination of plasma concentrations of carbamazepine and compare its feasibility with those used in routine analysis. The developed HPLC method was fully validated and the applicability of the proposed method was verified through the analysis of plasma samples of patients and later compared with the quantification of the same plasma samples with the CMIA method. The limit of quantification obtained was 0.5 μg/mL. The mean value for recovery was 99.05% and the coefficient of variation (CV) was 5.6%. The precision and accuracy of this method were within the acceptable limits; inter‐ and intraday CV values were <10%. The correlation between the CMIA method and the developed HPLC method was very good (r ≈ 0.999). A Bland–Altman plot showed no significant bias between the results. The HPLC‐DAD method may be an alternative to determine and monitoring the carbamazepine levels in human plasma or serum. Copyright © 2015 John Wiley & Sons, Ltd.     

The effects of secondary structure and O2 on the formation of direct strand breaks upon UV irradiation of 5-bromodeoxyuridine-containing oligonucleotides.

BACKGROUND: 5-Bromodeoxyuridine is a radiosensitizing agent that is currently being evaluated in clinical trials as an adjuvant in the treatment of a variety of cancers. gamma-Radiolysis and UV irradiation of oligonucleotides containing 5-bromodeoxyuridine result in the formation of direct strand breaks at the 5'-adjacent nucleotide by oxidation of the respective deoxyribose. We investigated the effects of DNA secondary structure and O2 on the induction of direct strand breaks in 5-bromodeoxyuridine-containing oligonucleotides. RESULTS: The efficiency of direct strand break formation in duplex DNA is dependent upon O2 and results in fragments containing 3'-phosphate and the labile 3'-ketodeoxyadenosine termini. The ratio of the 3'-termini is also dependent upon O2 and structure. Deuterium product isotope effects and tritium-transfer studies indicate that hydrogen-atom abstraction from the C1'- and C2'-positions occurs in an O2- and structure-dependent manner. CONCLUSIONS: The reaction mechanisms by which DNA containing 5-bromodeoxyuridine is sensitized to damage by UV irradiation are dependent upon whether the substrate is hybridized and upon the presence or absence of O2. Oxygen reduces the efficiency of direct strand break formation in duplex DNA, but does not affect the overall strand damage. It is proposed that the sigma radical abstracts hydrogen atoms from the C1'- and C2'-positions of the 5'-adjacent deoxyribose moiety, whereas the nucleobase peroxyl radical selectively abstracts the C1'-hydrogen atom from this site. This is the second example of DNA damage amplification by a nucleobase peroxyl radical, and might be indicative of a general reaction pattern for this family of reactive intermediates.     

Analysis of melamine resins by capillary zone electrophoresis with electrospray ionization-mass spectrometric detection

A method for the determination of the major components of (methoxymethyl)melamine resins, with quantitative analysis of unreacted melamine by capillary zone electrophoresis (CZE) using electrospray ionization-mass spectrometry (ESI-MS) is presented. Using a low background electrolyte (BGE) pH, components are separated according to their charge/ionic radius ratio with a distinctly different separation selectivity compared to the HPLC methods commonly employed in melamine-resin analysis. The use of a time-of-flight mass spectrometer (TOF-MS) was concluded to be necessary, as the complex samples studied required maximum sensitivity and resolution, which is clearly superior for TOF-MS detectors over their quadrupole counterparts. A standard curve of free melamine was determined with an R(2) = 0.999 over a concentration range of an order of magnitude. This method offers the unique separation selectivity of CZE as well as a quicker analysis time, especially for dimers compared to the HPLC methods used to date.     

Preference voting and project ranking using DEA and cross-evaluation

Cook and Kress (1990), using Data Envelopment Analysis (DEA) as their starting point, proposed a procedure to rank order the candidates in a preferential election. Notionally, each candidate is permitted to choose the most favourable weights to be applied to his/her standings (first place, second place, etc. votes) in the usual DEA manner with the additional ‘assurance region’ restriction that the weight for a j place vote should be more than that for a j +1 amount. We consider that this freedom to choose weights is essentially illusory when maximum discrimination between the candidates is sought, in which case the weights used to evaluate and rank the candidates are as if imposed externally at the outset. To avoid this, we present an alternative procedure which retains Cook and Kress' central idea but where, as well as using each candidate's rating of him/herself, we now make use of each candidate's ratings of all the candidates. We regard the so-called cross-evaluation matrix as the summary of a self- and peer-rating process in which the candidates seek to interpret the voters preferences as favourably for themselves, relative to the other candidates, as possible. The problem then becomes one of establishing an overall rating for each candidate from these individual ratings. For this, for each candidate, we use a weighted average of all the candidates ratings of that candidate, where the weights themselves are in proportion to each candidate's overall rating. The overall ratings are therefore proportional to the components of the principal (left-hand) eigenvector of the cross-evaluation matrix. These ideas are then applied to the selection of R & D projects to comprise an R & D program, thus indicating thier wider applicability.