A liquid chromatography‐tandem mass spectrometry method for the simultaneous determination of exemestane and its metabolite 17‐dihydroexemestane in human plasma

A simple and sensitive liquid chromatography‐tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the quantitation of exemestane (Exe) and its main metabolite 17‐dihydroexemestane (DhExe) in human plasma. The analytes were extracted by protein precipitation with acetonitrile, containing stable ¹³C‐labelled Exe (¹³C₃‐Exe) as internal standard, and measured by LC–MS/MS. The best chromatographic separationof the analytes from the interferences was achieved by using a Phenyl column operating under isocratic regime conditions. The total chromatographic runtime was 5.0 min and the elution of Exe and DhExe occurred at 2.5 min and 2.9 min, respectively. Quantitation was performed by employing the positive electrospray ionization (ESI) technique and multiple reaction monitoring mode (MRM). The monitored precursor to product‐ion transitions for Exe, DhExe and ¹³C₃‐Exe internal standard were m/z 297.0 → 120.8, m/z 299.1 → 134.9 and m/z 300.0 → 123.2, respectively. The lower limit of quantitation (LLOQ) was 0.1 ng/ml for DhExe and 0.2 ng/ml for Exe. The method was linear up to 36–51 ng/ml with r² ≥ 0.998. The intra‐ and inter‐assay precision were ≤7.7% and 5.1% for Exe and ≤8.1 and 4.9% for DhExe while deviations from nominal values were in the 1.5–13.2% and ? 9.0–5.8% ranges for Exe and DhExe, respectively. The analytical method resulted robust and suitable for pharmacokinetic monitoring of Exe and its main metabolite during adjuvant therapy in patients with breast cancer. Copyright © 2009 John Wiley & Sons, Ltd.     

Bromination of phenols in bromoperoxidase-catalyzed oxidations

Phenol and ortho-substituted derivatives furnish products of selective para-bromination, if treated with sodium bromide, hydrogen peroxide, and the vanadate(V)-dependent bromoperoxidase I from the brown alga Ascophyllum nodosum. Relative rates of bromination in morpholine-4-ethane sulfonic acid (MES)-buffered aqueous tert-butanol (pH 6.2) increase by a factor 32, as the ortho-substituent in a phenol changes from F via Cl, OCH₃, C(CH₃)₃, and H to CH₃. The polar effect in phenol bromination by the enzymatic method, according to a Hammett-correlation (ρ=−3), compares to reactivity of molecular bromine under identical conditions (ρ=−2). Hypobromous acid is not able to electrophilically substitute bromine for hydrogen at pH 6.2 in aqueous tert-butanol. The tribromide anion behaves in MES-buffered aqueous tert-butanol as electrophile (ρ∼−3), showing a similar polar effect in phenol bromination as molecular bromine.     

Sensing colorimetric approaches based on gold and silver nanoparticles aggregation: Chemical creativity behind the assay. A review

Localized surface plasmon resonance (LSPR) is one of the most remarkable features of gold nanoparticles (Au NPs) and silver nanoparticles (Ag NPs). Due to these inherent optical properties, colloidal solutions of Au and Ag NPs have high extinction coefficients and different colour in the visible region of the spectrum when they are well-spaced in comparison with when they are aggregated. Therefore, a well-designed chemical interaction between the analyte and NPs surroundings leads to a change of colour (red to blue for Au NPs and yellow to brown for Ag NPs from well-spaced to aggregated ones, respectively) allowing the visual detection of the target analyte.     

A Mechanism for Ionization of Nonvolatile Compounds in Mass Spectrometry: Considerations from MALDI and Inlet Ionization

Mechanistic arguments relative to matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) address observations that predominately singly charged ions are detected. However, recently a matrix assisted laser ablation method, laserspray ionization (LSI), was introduced that can use the same sample preparation and laser as MALDI, but produce highly charged ions from proteins. In MALDI, ions are generated from neutral molecules by the photon energy provided to a matrix, while in LSI ions are produced inside a heated inlet tube linking atmospheric pressure and the first vacuum region of the mass spectrometer. Some LSI matrices also produce highly charged ions with MALDI ion sources operated at intermediate pressure or high vacuum. The operational similarity of LSI to MALDI, and the large difference in charge states observed by these methods, provides information of fundamental importance to proposed ionization mechanisms for LSI and MALDI. Here, we present data suggesting that the prompt and delayed ionization reported for vacuum MALDI are both fast processes relative to producing highly charged ions by LSI. The energy supplied to produce these charged clusters/droplets as well as their size and time available for desolvation are determining factors in the charge states of the ions observed. Further, charged droplets/clusters may be a common link for ionization of nonvolatile compounds by a variety of MS ionization methods, including MALDI and LSI.     

Two color RNA intercalating probe for cell imaging applications

Here we report on a phenanthridine derivative which has a covalently linked fluorescein molecule in order to increase the light absorption and hence fluorescence signal intensity when bound to duplex RNA. Steady-state fluorescence shows that the energy transfer efficiency from the fluorescein to the phenanthridine fluorophore is approximately 77%, which results in the probe being over 5x brighter than other phenanthridine derivatives when bound to RNA. Due to the relatively long lifetime (approximately 20 ns) of the probe, time-resolved fluorescence is used to increase the signal to background ratio in cell growth medium from 7 (steady-state value) to over 40. Moreover, fluorescence images of cells containing the probe show that the fluorescein signal is readily apparent along with that of the intercalated fluorophore, allowing this probe to be used as a dual color probe which simultaneously reports the probes' location and that of RNA.     

Some new group divisible designs with block size 4 and two or three group sizes

Group divisible designs (GDDs) with block size 4 and at most 30 points are known for all feasible group types except three, namely $2^3{5}^4,3^5{6}^2$, and $2^2{5}^5$. In this paper we provide solutions for the first two of these three 4‐GDDs without assuming any automorphisms. We also construct several other 4‐GDDs. These include classes of 4‐GDDs of types ${\left(3m\right)}^4{\left(6m\right)}^q{\left(3n\right)}^1$ for $0\le n\le \left(q+1\right)m$ where $q\in \left\{2,3\right\}$ and solutions for 4‐GDDs of types $3^t{6}^s$ for a wide range of values of $s\ge 2,t\ge 4$ satisfying $t\equiv 0$ or $1\left(\mathrm{mod}4\right)$, including all cases with $4\le t\le s?1$. Most of the remaining unknown 4‐GDDs of type $3^t{6}^s$ have $\left(s?1\right)<t<2\left(s?1\right)$.     

Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo

Oxaliplatin is a very potent platinum(ii) drug which is frequently used in poly-chemotherapy schemes against advanced colorectal cancer. However, its benefit is limited by severe adverse effects as well as resistance development. Based on their higher tolerability, platinum(iv) prodrugs came into focus of interest. However, comparable to their platinum(ii) counterparts they lack tumor specificity and are frequently prematurely activated in the blood circulation. With the aim to exploit the enhanced albumin consumption and accumulation in the malignant tissue, we have recently developed a new albumin-targeted prodrug, which supposed to release oxaliplatin in a highly tumor-specific manner. In more detail, we designed a platinum(iv) complex containing two maleimide moieties in the axial position (KP2156), which allows selective binding to the cysteine 34. In the present study, diverse cell biological and analytical tools such as laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), isotope labeling, and nano-scale secondary ion mass spectrometry (NanoSIMS) were employed to better understand the in vivo distribution and activation process of KP2156 (in comparison to free oxaliplatin and a non-albumin-binding succinimide analogue). KP2156 forms very stable albumin adducts in the bloodstream resulting in a superior pharmacological profile, such as distinctly prolonged terminal excretion half-life and enhanced effective platinum dose (measured by ICP-MS). The albumin-bound drug is accumulating in the malignant tissue, where it enters the cancer cells via clathrin- and caveolin-dependent endocytosis, and is activated by reduction to release oxaliplatin. This results in profound, long-lasting anticancer activity of KP2156 against CT26 colon cancer tumors in vivo based on cell cycle arrest and apoptotic cell death. Summarizing, albumin-binding of platinum(iv) complexes potently enhances the efficacy of oxaliplatin therapy and should be further developed towards clinical phase I trials.

Albumin-targeting of a maleimide-containing oxaliplatin-releasing platinum(iv) prodrug results in tumor-specific drug delivery and activity as shown by LA-ICP-MS, isotope-labeling and NanoSIMS in cell culture and in vivo.     

Highly Oriented Pyrolytic Graphite as a Platform for Atomic Absorption Spectrometry

Compared to pyrolytic graphite (PG) and pyrolytically coated polycrystalline graphite (PCPG), which are commonly employed substrates for graphite furnace atomic absorption spectrometry (GFAAS), highly oriented pyrolytic graphite (HOPG) is characterized by a high degree ofc-axis alignment with relatively few active sites and imperfections present on the surface. The usefulness of HOPG and commercial PG platforms for the determination of lead, copper, and aluminum by GFAAS was compared. Qualitative comparison of the absorption profiles and temperature optimizations suggest that lead, copper with a chemical modifier (palladium), and aluminum interact similarly with the two graphite substrates, while copper without a modifier interacts less strongly with HOPG than with PG. These results are in agreement with previous studies that have demonstrated that copper interacts strongly with PG and PCPG. HOPG and PG were employed for the determination of a pine needles standard reference material (SRM) and Fraser fir (Abies fraseri) samples. The analyses of the SRM gave good agreement with the certified value using both substrates, and comparable values were obtained for the samples. These results suggest that HOPG may be useful as a model for PG or PCPG when techniques such as scanning tunneling microscopy that require a high degree ofc-axis alignment are employed.     

Oxidation of solid aluminium silicon alloys in air

The kinetics of oxidation of solid Al–Si alloys in air was studied at temperature interval between 490 °C and 532 °C. The initial time intervals in which oxidation is governed by a parabolic quadratic low were found form the weight time-gain curves. At temperature higher than 512 °C the exponent of the parabolic ratio differs from 2. It was shown the influence of the alloying element Si on the oxidation and the effective activation energies of oxidation of Al Si alloys were calculated. They are considerably higher than the effective activation energies for pure aluminium.     

Zur oxidativen Addition von 1-Halogenalk-1-inen – Synthese und Struktur von Phenylalkinylpalladium-Komplexen

On the Oxidative Addition of 1-Halogenalk-1-ynes – Synthesis and Structure of Phenylalkynylpalladium Complexes [Pd(PPh₃)₄] ( 2 ) reacts with IC≡CPh and ClC≡CPh in the sense of an oxidative addition to give trans-[Pd(C≡CPh)X(PPh₃)₂] (X = I: 3 a , X = Cl: 3 b ). As side products trans-[PdX₂(PPh₃)₂] (X = I: 4 a , X = Cl: 4 b ; < 10%) and PhC≡C–C≡CPh ( 5 ; X = I: ca 30%, X = Cl: < 4%) are formed. 3 a and 3 b were characterized by NMR (¹H, ¹³C, ³¹P) and IR spectroscopies as well as by X-ray single-crystal structure analyses. In the crystals of 3 a and 3 b isolated molecules were found. The Pd–C≡C–Ph unit is linear in 3 a and approximately linear in 3 b [Pd–C≡C 174.2(6)°, C≡C–C 179,0(7)°].