Novel gallium(III) complexes containing phthaloyl derivatives of neutral aminoacids with apoptotic activity in cancer cells

The reaction of N-phthaloylglycine and N-phthaloyl-dl-alanine with trimethylgallium (1:1) yielded the dinuclear complexes [Me₂Ga(μ-O₂CCH₂N(CO)₂C₆H₄)]₂ (1) and RS-[Me₂Ga(μ-O₂CCHMeN(CO)₂C₆H₄)]₂ (2), respectively. The molecular structure of 2 was determined by X-ray diffraction studies. The cytotoxic activity of the organogallium(III) complexes (1 and 2) was tested against human tumour cell lines 8505C anaplastic thyroid cancer, A253 head and neck tumour, A549 lung carcinoma, A2780 ovarian cancer, DLD-1 colon carcinoma and compared with that of cisplatin.The best response of the synthesized gallium complexes, compared with that of cisplatin, was observed against 8505C anaplastic thyroid cancer and DLD-1 colon carcinoma, while the best IC₅₀ values were found for A253 head and neck carcinoma. While the studied carboxylic acids show no proliferative activity, complexes 1 and 2 present very similar cytotoxic activity against all the studied cancer cell lines (IC₅₀ from ca. 5 to 25 μM). The cytotoxicities of complexes 1 and 2 are in all cases higher than that presented by gallium(III) nitrate. In addition DNA laddering method showed that treatment of the studied cell lines with IC₉₀ doses of 1 and 2 resulted in the induction of apoptotic mode of cell death.     

Sequential injection system for phospholipase A2 activity evaluation: Studies on liposomes using an environment-sensitive fluorescent probe

This work reports the development of an automatic methodology based on the use of 1-anilinonaphthalene-8-sulfonate (ANS) as an interfacial fluorescent probe for detecting the hydrophobic environment shift around the probe, caused by the hydrolytic action of PLA₂ on the liposomes. The implementation of this reaction in a sequential injection analysis (SIA) system along with the use of the mixing chambers permitted the evaluation of PLA₂ activity and assessment of the inhibitory effect of the non-steroidal anti-inflammatory drugs (NSAIDs) on PLA₂ activity.Several studies were performed with the aim of establishing the appropriate flow system configuration: the liposome substrate; PLA₂ and ANS optimum concentrations and incubation times before and after the enzyme addition. Based on these studies, the optimum reaction conditions were selected. It was shown that PLA₂ is effectively inhibited by the NSAIDs tested (meloxicam, tolmetin and ibuprofen) and by the α-lipoic acid, used as a positive control.Results obtained from the flow system are in agreement with those provided by the comparison batch procedures. The proposed methodology is in fact more efficient and rapid than the comparison batch experiments, enabling the exact timing of fluidic manipulations and precise control of the reaction conditions.     

Capillary electrochromatographic separation of illicit drugs employing a cyano stationary phase

In this study, we present a capillary electrochromatographic method for separation of basic compounds of interest in forensic science (amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, cocaine, codeine, heroin, morphine, and 6-monoacethylmorphine). Several analytical conditions were taken into account to completely separate in the same run the 10 drugs of abuse analyzed. Chromatographic retention, selectivity and efficiency were evaluated in dependence of the type of stationary phase (CN and RP-C₁₈ derivatized silica particles), mobile phase composition, buffer type and pH, sample injection. The optimum separation parameters were set up using a mixture of aqueous sodium phosphate buffer (pH 2.5)/acetonitrile (80/20, v/v) as the mobile phase, 10 kV and 20 °C as applied voltage and capillary temperature, respectively. Under these conditions all the studied analytes were baseline resolved within 20 min. The method performance was investigated in terms of precision, linearity, sensitivity and accuracy to demonstrate the applicability of the developed capillary electrochromatographic system to forensic analysis. Calibration curves provided a good linearity over a working range of 100–1200 ng/mL for all analytes. Limits of detection and quantification were in the range 5–12 ng/mL and 10–30 ng/mL, respectively. Then the method was applied to the analysis of a human urine sample spiked with a basic compounds’ mixture. Urine samples’ pre-treatment was carried out through a solid phase extraction (SPE) procedure on strong cation exchange (SCX) cartridges.     

Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

Highly effective : We report herein the first and highly efficient total syntheses of norzoanthamine and zoanthamine in full detail, which involves stereoselective synthesis of the requisite triene for an intramolecular Diels–Alder reaction via three‐component coupling reactions, the intramolecular Diels–Alder reaction, and subsequent crucial bis‐aminoacetalization as the key steps.

     

Study on synthesis and distribution in vivo of 5-Fu-cholic acid conjugate

A series of hepatic targeting drugs,5-Fu-cholic acid conjugate T1-T5,were synthesized.5-Fu and cholic acid was selected as starting material,after N-hydroxymethylation,condensation,hydrogenolysis to obtain carboxylated 5-Fu 5a--e.Carboxylated 5-Fu 5a--e were eondensated with intermediate 3-hydroxyethyl cholic acid benzyl ester 6 to get 7a-e,7a-e were deproteeted to get T1-T5.     

Affinity Capillary Electrophoresis Studies on the Influence of Alcohols on the Interaction of β-Cyclodextrin with Non-Steroidal Anti-Inflammatory Drugs

Summary The influences of methanol, ethanol, 1-propanol and 1-butanol on the binding constants of -cyclodextrin (-CD) with non-steroidal anti-inflammatory drugs such as acemetacin, indometacin, cinmetacin, sulindac and diclofenac sodium and the separation of these drugs were studied by affinity capillary electrophoresis. No obvious effect was observable upon addition of methanol up to 6% (v/v) in the running buffer, while the addition of other alcohols at the concentration of 2% resulted in obvious decrease in the binding constants of -CD with acemetacin, indometacin, cinmetacin and sulindac. With an increasing chain length of added alcohols, all of these changes increased. Upon additions of different alcohols in the running buffer the change of the binding constant of -CD with diclofenac sodium was inconspicuous. Based on these results, the separation conditions for these drugs were optimized. The presence of 6% methanol in the running buffer containing 3 mM -CD was helpful to the baseline separation of these drugs. The electrophorograms of these drugs in the presence of ethanol, 1-propanol and 1-butanol showed a worse separation due to the decrease in the binding constants. The methods for the separation of these drugs and the study on the binding constants possess the advantages of easy performance, high speed and low sample consumption. AcknowledgementThe authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No.20275017), the Science Foundation of Jiangsu (No.BS2001063) and the Key Project of Cancer Institute of Jiangsu Province.     

Orthogonal array designs for the optimization of liquid-liquid-liquid microextraction of nonsteroidal anti-inflammatory drugs combined with high-performance liquid chromatography-ultraviolet detection

Orthogonal array designs (OADs) were applied for the first time to optimize liquid-liquid-liquid microextraction (LLLME) conditions for the analysis of three nonsteroidal anti-inflammatory drug residues (2-(4-chlorophenoxy)-2-methylpropionic acid, ketoprofen, and naproxen) in wastewater samples. Six relevant factors were investigated: type of organic solvent, composition of donor phase and acceptor phase, stirring speed, extraction time and salt concentration. In the first stage, mixed-level orthogonal array design, an OA16 (4(1) x 2(12)) matrix was employed to study the effect of six factors, by which the effect of each factor was estimated using individual contributions as response functions. Based on the results of the first stage, 1-octanol was chosen as organic solvent for extraction. The other five factors were selected for further optimization using an OA16 (4(5)) matrix and a 4 x 4 table to locate more exact levels for each variable. The relative standard deviations for the reproducibility of optimized LLLME varied from 6.2 to 7.1%. The coefficients of determination for calibration curves were higher than 0.9950. The method detection limits for drugs spiked in ultrapure water were in the range of 0.03-0.3 ng/mL. The final optimized conditions were applied to the analysis of drug residues in three wastewater samples in Singapore.