Novel zirconocene anticancer drugs?

From the reaction of Super Hydride (LiBEt₃H) with 6-(4-methoxyphenyl) fulvene (1a), 6-(2-fluoro-4-methoxyphenyl) fulvene (1b), and 6-(4-N,N-dimethylaminophenyl) fulvene (1c) lithiated cyclopentadienide intermediates (2a-c) were synthesised. These intermediates were then transmetallated to zirconium with ZrCl₄ to give benzyl-substituted zirconocenes bis-[(4-methoxybenzyl)cyclopentadienyl] zirconium(IV) dichloride (3a), bis-[(2-fluoro-4-methoxybenzyl)cyclopentadienyl] zirconium(IV) dichloride (3b) and bis-[(4-N,N-dimethylaminobenzyl)cyclopentadienyl] zirconium(IV) dichloride (3c). All three zirconocenes were characterised by single crystal X-ray diffraction and preliminary in vitro cell tests were performed with the zirconocene derivatives on the LLC-PK cell line in order to determine their cytotoxicity. Zirconocenes 3b and 3c did not show cytotoxicity up to a concentration of 170 μM, while 3a exhibited an IC50 value of 57 μM against LLC-PK.     

Anticancer drugs based on alkenyl and boryl substituted titanocene complexes

The alkenyl-substituted titanocene complex [Ti(η⁵-C₅H₅)(η⁵-C₅H₄{CMe₂(CH₂CH₂CHCH₂)})Cl₂] (1) has been synthesized and characterized using traditional methods. The reaction of 1 with 9-BBN gave the boryl substituted complex [Ti(η⁵-C₅H₅)(η⁵-C₅H₄{CMe₂(CH₂CH₂CH₂CH₂BC₈H₁₄)})Cl₂] (2). The cytotoxic activity of 1 and 2 was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, human breast carcinoma MDA-MB-361 and normal immunocompetent cells peripheral blood mononuclear cells PBMC and compared with those of the reference complexes [Ti(η⁵-C₅H₅)₂Cl₂] (R1), [Ti(η⁵-C₅H₄Me)₂Cl₂] (R2) and [Ti(η⁵-C₅H₅)(η⁵-C₅H₄SiMe₃)Cl₂] (R3). Complex 1 showed higher cytotoxic activities on HeLa, Fem-x and K562 (IC₅₀ values from 96.6 ± 3.4 to 149.2 ± 2.9 μM) than the reference complexes R1, R2 and R3 which presented IC₅₀ values from 173.3 ± 6.0 to >200 μM. On the other hand, boryl substituted complex 2, present slightly lower cytotoxic activities than 1 on HeLa, Fem-x and K562 (IC₅₀ values from 155.6 ± 5.5 to 167.9 ± 4.2 μM). However, 2 was the most active of the studied complexes against MDA-MB-361 (IC₅₀ value of 161.1 ± 0.1 μM). Structural studies based on DFT calculations of 1 and 2 have also been carried out in order to gain a possible insight into the relationship between metal complex structure and cytotoxicity.     

Comparison of molecularly imprinted,mixed-mode and hydrophilic balance sorbents performance in the solid-phase extraction of amphetamine drugs from wastewater samples for liquid chromatography–tandem mass spectrometry determination

Recent studies have shown that amphetamines and other drugs of abuse residues occur in wastewater. Consequently, several methods have been developed for their determination by solid-phase extraction (SPE) and liquid chromatography–tandem mass spectrometry (LC–MS/MS). However, a major drawback of these methods is the lack of selectivity during SPE that results in reduced sensitivity, due to matrix effects, and in some cases in low precision and poor accuracy. In order to tackle this problem, three different SPE alternatives have been evaluated in this work for the determination of five amphetamines: common hydrophilic balance (Oasis HLB), mixed-mode (Oasis MCX) and molecularly imprinted polymers (MIPs) sorbents. Among them, Oasis HLB showed the worst performance, as three amphetamines (MDA, MDMA and MDEA) could not be determined because of interfering signals in the LC–MS/MS chromatogram, and amphetamine recoveries could not be corrected by the use of the deuterated analogue internal standard. Oasis MCX permitted the determination of all target analytes, but with still strong signal suppression: ca. 70% signal drop with wastewater samples, which could in this case be corrected by the internal standards providing acceptable trueness (overall recoveries: 101–137%), precision (RSD: 2.0–12%) and limits of detection (LOD: 1.5–4.4 ng/L). Alternatively, MIPs rendered cleaner extracts with less matrix effects (ca. 30% signal drop), and thus lower LODs (0.5–2.7 ng/L) and even better trueness (91–114% overall recovery) and precision (1.5–4.4%RSD). The final application of the method with MIP cartridges showed the presence of MDA and MDMA in the seven analysed wastewaters at the 4–20 ng/L level.     

Recent Advances in the Chemistry and Biology of Naturally Occurring Antibiotics

Ever since the world‐shaping discovery of penicillin, nature's molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug‐development stories, the overwhelming majority of which have their origin in natural products. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on total synthesis, analogue design, and biological evaluation of molecules with novel mechanisms of action.     

Development and validation of an HPLC method for the determination of seven penicillin antibiotics in veterinary drugs and bovine blood plasma

Herein a quantitative method for the determination of seven penicillins in bovine plasma and veterinary drugs has been developed. Amoxicillin (AMO), ampicillin (AMP), penicillin G (PENG), penicillin V (PENV), oxacillin (OXA), cloxacillin (CLO) and dicloxacillin (DICLO) were separated on a Perfectsil ODS‐2 (250×4 mm, 5 μm) column, using gradient elution, with a mobile phase of 0.1% v/v TFA and ACN–methanol (90:10 v/v). PDA detection was used at 240 nm. Penicillins were isolated from bovine plasma by SPE on Lichrolut RP‐18 cartridges with mean recoveries from 85.7 to 113.5%. Colchicine (3 ng/μL) was used as an internal standard. The developed method was validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity. Repeatability (n = 5) and between‐day precision (n = 5) revealed RSD < 12%. The detection limits in the bovine plasma were estimated as 18 ng for AMO and AMP, 25 for PENG, PENV and OXA, 3 ng for CLO and 12 ng for DICLO. Spiked plasma samples were stable for 1 wk, except for AMP and CLO, which were stable for 3 wk and OXA for 4 wk. AMO, PENG and PENV were stable for two freeze–thaw cycles, OXA, CLO and DICLO for four, while AMP only for one.     

Local linear regression for data with AR errors

In many statistical applications, data are collected over time, and they are likely correlated. In this paper, we investigate how to incorporate the correlation information into the local linear regression. Under the assumption that the error process is an auto-regressive process, a new estimation procedure is proposed for the nonparametric regression by using local linear regression method and the profile least squares techniques. We further propose the SCAD penalized profile least squares method to determine the order of auto-regressive process. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed procedure, and to compare the performance of the proposed procedures with the existing one. From our empirical studies, the newly proposed procedures can dramatically improve the accuracy of naive local linear regression with working-independent error structure. We illustrate the proposed methodology by an analysis of real data set.     

Two‐dimensional chemotaxis models with fractional diffusion

In this paper we study the Cauchy problem for the fractional diffusion equation u_t + (?Δ)^α/2u=?·(u?(Δ^?1u)), generalizing the Keller–Segel model of chemotaxis, for the initial data u₀ in critical Besov spaces ?(?²) with r∈[1, ∞], where 1<α<2. Making use of some estimates of the linear dissipative equation in the frame of mixed time–space spaces, the Chemin ‘mono‐norm method,’ Fourier localization technique and the Littlewood–Paley theory, we obtain a local well‐posedness result. We also consider analogous ‘doubly parabolic’ models. Copyright © 2008 John Wiley & Sons, Ltd.     

A characteristic finite element method with local mesh refinements for the Lamm equation in analytical ultracentrifugation

The Lamm equation is a fundamental differential equation in analytical ultracentrifugation, for describing the transport of solutes in an ultracentrifuge cell. In this article, we present a characteristic finite element method with local mesh refinements for solving the Lamm equation. The numerical method is mass‐conservative by design and allows relatively large time steps to be used. Numerical experiments indicate that the numerical solutions are oscillation‐free in the region near the cell bottom, where mass build up and large concentration gradients occur. Positivity of solutions is also well kept. © 2008 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq, 2009     

A powerful route minimization heuristic for the vehicle routing problem with time windows

We suggest an efficient route minimization heuristic for the vehicle routing problem with time windows. The heuristic is based on the ejection pool, powerful insertion and guided local search strategies. Experimental results on the Gehring and Homberger’s benchmarks demonstrate that our algorithm outperforms previous approaches and found 18 new best-known solutions.     

Notes on local o‐minimality

We introduce and study some local versions of o‐minimality, requiring that every definable set decomposes as the union of finitely many isolated points and intervals in a suitable neighbourhood of every point. Motivating examples are the expansions of the ordered reals by sine, cosine and other periodic functions (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)