Temsirolimus metabolic pathways revisited.

Temsirolimus, a derivative of sirolimus, exhibits potent antitumor properties. It was the goal of this study to identify yet unknown temsirolimus metabolites generated after incubation with human liver microsomes. Previously, 23-hydroxy-, 24-hydroxy, 12-hydroxy, hydroxy-piperidine and 27-O-desmethyl temsirolimus had been described.Metabolite structures were identified using high-resolution mass spectrometry, MS/iontrap (MSn) and comparison of fragmentation patterns of the metabolites with those of temsirolimus and other known sirolimus derivatives. Moreover, enzyme kinetic parameters of temsirolimus metabolite formation as well as the contribution of individual recombinant cytochrome P450 (CYP) enzymes to temsirolimus metabolism were investigated.Human liver microsomes mainly hydroxylated and/or demethylated temsirolimus. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O-desmethyl, 16-O-desmethyl and 27-O-desmethyl temsirolimus; hydroxylated metabolites: hydroxy piperidine temsirolimus, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 45/46-hydroxy and 49-hydroxy temsirolimus; demethylated-hydroxylated metabolites: 16-O-desmethyl, 24-hydroxy; 16-O-desmethyl, 23-hydroxy and 16-O-desmethyl 46-hydroxy temsirolimus; didemethylated metabolite: 27,39-O-didesmethyl temsirolimus; and dihydroxylated metabolite: 12,24-dihydroxy temsirolimus. It was confirmed that CYP3A4 represents the predominant enzyme responsible for temsirolimus metabolism. Moreover, CYP3A5 as well as CYP2C8 also showed significant activities especially resulting in the formation of 27-O-desmethyl, 25-hydroxy and hydroxy-piperidine temsirolimus.It is concluded that temsirolimus is metabolized to more than 20 metabolites, not counting metabolism via the sirolimus pathway. Eighteen of these metabolites could be structurally identified using ion trap MSn and high-resolution mass spectrometry. Moreover, the present study showed that, in addition to CYP3A4, metabolism via CYP3A5 and CYP2C8 also represent significant metabolic pathways.

Fully digital workflow for presurgical orthodontic plate in cleft lip and palate patients.

OBJECTIVE: In most cases, according to our treatment concept, a presurgical orthodontic treatment (POT) is performed on patients with cleft lip and palate (CLP). The aim of this case report is to demonstrate a completely digital workflow for the production of a palate plate. MATERIALS AND METHODS: For the assessment of the maxillary arch, a digital impression of the jaw was made on two patients with an intraoral scanner (Cerec Omnicam Ortho). After reconstruction of a virtual model from the scan data, appropriate areas of the jaw could be blocked out and a plate constructed. This was printed with a DLP three-dimensional (3D) printer (SHERA EcoPrint D30) with class IIa biocompatible material. After minor surface finishing, the plates could be incorporated in the patients' mouths. RESULTS: The scans could be performed in a short time without affecting the very young patients. All clinically relevant areas for the production and digital measurement of the models could be recorded. The plates showed an extremely good fit, and there were no differences in wear compared with a conventionally manufactured plate. CONCLUSION: For the first time, a risk-free digital impression of the edentulous jaw in CLP babies with a subsequently completely digitally constructed and 3D-printed palatal plate could be shown.

Generation of Aryl Radicals through Reduction of Hypervalent Iodine(III) Compounds with TEMPONa: Radical Alkene Oxyarylation.

A novel method for selective generation of aryl radicals from diaryliodonium salts and iodanylidene malonates with sodium 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPONa) as a single-electron transfer (SET) reducing reagent is described. In the presence of various alkenes, aryl radicals formed after SET-reduction of hypervalent iodine compounds undergo alkene addition and the adduct radicals that are thus generated are efficiently trapped by the concomitantly generated TEMPO radical to eventually afford oxyarylated products in moderate to very good yields. The efficiency of aryl radical generation of various iodine(III) reagents is studied and the generation of an iodanylidene malonate aryl radical is also investigated by computational methods.

Radical aminooxygenation of alkenes with N-fluoro-benzenesulfonimide (NFSI) and TEMPONa.

Reaction of various alkenes with commercially available N-fluorobenzenesulfonimide (NFSI) and TEMPONa provides the corresponding aminooxygenation products in moderate to good yields. Single electron transfer from readily generated TEMPONa to NFSI allows for clean generation of the corresponding bissulfonylamidyl radical along with TEMPO. N-radical addition to an alkene and subsequent TEMPO trapping provides the corresponding aminooxygenation product.

Preparation of phenanthrenes from ortho-amino-biphenyls and alkynes via base-promoted homolytic aromatic substitution.

A transition-metal-free phenanthrene synthesis starting from readily accessible ortho-amino-biaryls is presented. The biarylamines are in situ transformed into the corresponding diazonium salts which upon single electron reduction give the corresponding aryl radicals. Addition to an alkyne and subsequent base promoted homolytic aromatic substitution (BHAS) provide phenanthrenes in moderate to good yields.

Cyclizing radical carboiodination, carbotelluration, and carboaminoxylation of aryl amines.

Radical carboiodination of various aryl amines is reported. Aryl diazonium salts, generated in situ from the corresponding aryl amines, are reacted with Bu4NI to provide the corresponding aryl radicals which undergo 5-exo or 6-exo cyclization. Iodine abstraction eventually affords the carboiodinated products in good to excellent yields. If TEMPO is added, the cascade provides the cyclized carboaminoxylation products. Running the reaction in the presence of PhTeTePh affords the phenyltellurated cyclized products.

Catalytic regioselective oxidation of glycosides.

Discrimination among equals: A catalytic method for the selective oxidation of unprotected glycosides, both monosaccharides and disaccharides, has been developed. The resulting ketosaccharides are isolated in moderate to excellent yields. This approach provides a basis for protecting-group-free synthetic transformations of carbohydrates.

Transition-metal-free oxyarylation of alkenes with aryl diazonium salts and TEMPONa.

The reaction of readily available TEMPONa with aryl diazonium salts allows for clean generation of the corresponding aryl radicals along with TEMPO. Aryl radical addition to alkenes with subsequent TEMPO trapping provides the corresponding oxyarylation products in good to excellent yields. These experimentally easy to conduct transformations occur in the absence of any transition metal under mild conditions, and the process shows broad functional group compatibility.

Simple and rapid quantification of gadolinium in urine and blood plasma samples by means of total reflection X-ray fluorescence (TXRF).

A simple and rapid method to determine gadolinium (Gd) concentrations in urine and blood plasma samples by means of total reflection X-ray fluorescence (TXRF) was developed. With a limit of detection (LOD) of 100 µg L(-1) in urine and 80 µg L(-1) in blood plasma and a limit of quantification (LOQ) of 330 µg L(-1) in urine and 270 µg L(-1) in blood plasma, it allows analyzing urine samples taken from magnetic resonance imaging (MRI) patients during a period of up to 20 hours after the administration of Gd-based MRI contrast agents by means of TXRF. By parallel determination of the urinary creatinine concentration, it was possible to monitor the excretion kinetics of Gd from the patient's body. The Gd concentration in blood plasma samples, taken immediately after an MRI examination, could be determined after rapid and easy sample preparation by centrifugation. All measurements were validated with inductively coupled plasma mass spectrometry (ICP-MS). TXRF is considered to be an attractive alternative for fast and simple Gd analysis in human body fluids during daily routine in clinical laboratories.