One‐step reductive etherification of 4‐[18F]fluoro‐benzaldehyde with decaborane

Reductive coupling reactions between 4‐[¹⁸F]fluoro‐benzaldehyde ([¹⁸F] 1 ) and different alcohols by use of decaborane (B₁₀H₁₄) as reducing agent have the potential to synthesize 4‐[¹⁸F]fluoro‐benzylethers in one step. [¹⁸F] 1 was synthesized from 4‐trimethylammonium benzaldehyde (triflate salt) via a standard fluorination procedure (K[¹⁸F]F/Kryptofix^® 222) in dimethylformamide at 90°C for 25 min and purified by solid‐phase extraction. Subsequently, reductive etherifications of [¹⁸F] 1 were performed as one‐step reactions with primary and secondary alcohols, mediated by B₁₀H₁₄ in acetonitrile at 60°C. Various 4‐[¹⁸F]fluorobenzyl ethers (6 examples are shown) were obtained within 1–2 h reaction time in decay‐corrected radiochemical yields of 12–45%. Copyright © 2006 John Wiley & Sons, Ltd.     

洛索洛芬钠合成工艺研究Ⅱ.高区域选择性烷基化合成法

在叔丁醇钠和二甲基亚砜的存在下,2-(对溴甲基苯基)丙酸对2-乙氧羰基环戊酮进行C-烷基化,再经水解脱羧,成盐即得洛索洛芬钠,以2-(对溴甲基苯基)丙酸计算,总收率为72%。探索了不同溶剂和反应温度对烷基化收率的影响。     

Non-cytochrome P450-mediated bioactivation and its toxicological relevance

The bioactivation of drugs is often associated with toxicological outcomes; however, for most cases, the causal relationship between bioactivation and toxicity is not well established despite extensive research that attempts to elucidate the mechanisms leading to the formation of chemically reactive species, presumably the initial step towards adverse reactions. Due to rapid advancement in the research of cytochrome P450s (CYPs) and the prevalence of CYP involvement in the metabolic clearance of pharmaceuticals, CYP-mediated bioactivation is widely investigated and reviewed, while non-CYP-mediated bioactivation has not been emphasized. The widespread use of metabolic stability screening in drug discovery, however, has led to the identification of new chemical entities that rely on non-CYP enzymes for clearance, and the number of drugs that undergo metabolism via these enzymes has increased. Non-CYP enzymes can be divided into four general categories according to their enzymatic function, namely, oxidative, reductive, conjugative and hydrolytic. The aim of this review is to complement the existing literature on CYP-mediated metabolism by focusing on bioactivation mediated non-CYP enzymes and provide representative examples in each category.     

水杨羟肟酸功能化聚苯乙烯的制备及其与Tb(Ⅲ)离子配合物的荧光发射特性初探

凭借氯甲基化的聚苯乙烯（CMPS）与水杨羟肟酸（SHA）之间的Friedel-Crafts烷基化反应,使SHA键合在聚苯乙烯( PS) 的侧链上,制备了改性聚苯乙烯(SHA/PS)。再使SHA/PS 与Tb(Ⅲ) 离子配位,制得高分子-稀土配合物Tb(Ⅲ)-SHA/PS。采用红外光谱对其结构进行了表征,考察了影响SHA与CMPS之间Friedel-Crafts 烷基化反应的主要因素。结果表明,当催化剂SnCl4用量为0.06 mL,35 ℃反应18 h时,SHA/PS上SHA的键合率高达33.1%。Tb(Ⅲ)-SHA/PS配合物不仅具有与Tb(Ⅲ)离子相似的荧光光谱,而且SHA/PS配体对Tb(Ⅲ)离子产生了显著的Antenna效应,使其荧光强度大幅增强。     

Methionine329 in human serum albumin: A novel target for alkylation by sulfur mustard

Exposure to the vesicant sulfur mustard (SM) may lead to erythema and blistering. Toxicity of SM is hypothesized due to the alkylation of DNA bases and nucleophilic amino acid side chains in proteins (adducts) by forming the hydroxyethylthioethyl (HETE) moiety. Despite its prohibition by the chemical weapons convention, SM still represents a serious threat to military personnel and civilians. Therefore, development and improvement of forensic analytical methods for the verification of SM exposure is of high interest. Protein adducts have been shown to be highly suitable and beneficial biomarkers of poisoning. Herein we present methionine³²⁹ in human serum albumin (HSA) as a novel target of SM forming a HETE‐methionyl sulfonium ion. The alkylated tetrapeptide LeuGlyMet³²⁹(‐HETE)Phe, LGM(‐HETE)F, was detected after pepsin‐mediated proteolysis and subsequent analysis by microbore liquid chromatography–electrospray ionization–high‐resolution tandem‐mass spectrometry. Compound identity was confirmed by a synthetic reference. Proteolysis conditions for HSA were optimized towards maximum yield of LGM(‐HETE)F and its limit of identification (32.3 nM SM in serum) was similar to those of the established HSA‐derived biomarkers HETE‐CysPro and HETE‐CysProPhe (15.6 nM SM in serum). Stability of the alkylated Met³²⁹ in vitro and in vivo was limited to 5 days making this modification a beneficial short‐time biomarker. Furthermore, it was found that the HETE‐methionyl sulfonium ion can transfer its HETE moiety to the side chain of cysteine and glutamic acid as well as to the N‐terminus of peptides and proteins in vitro thus revealing novel insights into the molecular toxicity of SM.     

Adsorptive-Oxidative Removal of Sulfides from Water by MnO2-Loaded Carboxylic Cation Exchangers

Hybrid ion exchangers (HIX) containing manganese(IV) oxide (MnO₂) based on macroporous and gel-type carboxylic cation exchangers as supporting materials were obtained. The hybrid materials were characterized using scanning electron microscopy with energy dispersive spectrometry (SEM/EDS), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD) and nitrogen adsorption isotherms at 77 K and mercury porosimetry. HIX with introduced MnO₂ (20.0–32.8 wt% Mn) were tested for removal of dissolved sulfides from anoxic aqueous solutions with 100–500 mg S²⁻/dm³ concentrations. The process proceeded effortlessly at pH 10–13 despite unfavorable electrostatic interactions of the reactants. The highest exhibited sorption capacity was 144.3 ± 7.1 mg S²⁻/g. Approximately 65% of dissolved sulfides were oxidized to S₂O₃²⁻ ions and repelled from HIX structure. On average, 13% of sulfide removal products were adsorbed by the MnO₂ surface. The impact of MnO₂ load and the ionic form of HIX functional groups on removal of sulfides and resulting products was examined. The mechanism of the process is suggested.     

Development of an automated,GMP compliant FASTlab™ radiosynthesis of [18F]GE-179 for the clinical study of activated NMDA receptors

N-(2-chloro-5-(S-2-[¹⁸F]fluoroethyl)thiophenyl)-N'-(3-thiomethylphenyl)-N'-methylguanidine, ([¹⁸F] GE-179 ), has been identified as a promising positron emission tomography (PET) ligand for the intra-channel phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The radiosynthesis of [¹⁸F] GE-179 has only been performed at low radioactivity levels. However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlab™ radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two-step process, involving the nucleophilic fluorination of ethylene ditosylate, 11 , followed by alkylation to the deprotonated thiol precursor, N-(2-chloro-5-thiophenol)-N'-(3-thiomethylphenyl)-N'-methyl guanidine, 8 . The crude product was purified by semi-preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 μg. The final formulation volume was 14 mL. The previously described radiosynthesis of [¹⁸F] GE-179 was successfully modified to deliver an process on the FASTlab™ that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.     

Evaluation of the fructosamine test for the measurement of plasma protein glycation

Summary Repeated estimation of plasma protein glycation by the fructosamine assay gave more variable results than expected from analytical variablility (coefficient of variation approximately 2%). Fructosamine results obtained on plasma samples drawn at different times of the day differed by up to 1 mmol/l, corresponding to a coefficient of variation of greater than 10%. As a consequence, the information concerning averaged glycaemia of a fructosamine determination is subject to an uncertainty of 7.8 mmol/l. Fructosamine concentrations were linearly related to the protein concentration. Correction for the protein concentration decreased this variability; however, factors other than protein concentration, such as lipid content, also influence results of fructosamine determinations.     

Expression of human O6-methylguanine-DNA methyltransferase in Chinese hamster ovary cells and restoration of cellular resistance to certain N-nitroso compounds.

We have constructed a plasmid in which the expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA is driven by the Rous sarcoma virus promoter sequence. Transfection of this plasmid into Chinese hamster ovary (CHO) cells results in expression of MGMT and in cellular resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 1-(2-chloroethyl)-1-nitrosourea (CNU), but not to N-nitroso-N-ethylurea. The specific activity of MGMT in transfected CHO cells correlated well with their resistance to MNNG and CNU. Southern analysis showed that the plasmid had been integrated into the CHO cell genome. Western analysis of extracts from transfected CHO cells using an antibody against a peptide corresponding to the carboxyl-terminal end of the human MGMT protein demonstrated a single band with a molecular size of 24-25 kDa; no such band was observed in extracts from wild-type CHO cells. These transfected cells may therefore be used to study the role of MGMT in the repair of alkylating DNA lesions and to determine its importance in carcinogenesis as well as in chemotherapy.