Technische Verfahren zur Synthese von Carotinoiden und verwandten Verbindungen aus 6-Oxo-isophoron. II. Ein neues Konzept für die Synthese von (3RS, 3′RS)-Astaxanthin

Technical Procedures for the Synthesis of Carotenoids and Related Compounds from 6-Oxo-isophorone. II. A Novel Concept for the Synthesis of (3RS, 3′RS)-Astaxanthin Starting from 6-oxo-isophorone ( 2 ) a new concept for a seven-step synthesis of (3RS, 3′RS)-astaxanthin ( 1 ) has been developed. As a key feature of the new approach, the oxidation state of astaxanthin ( 1 ) is adjusted already at an early stage of the synthesis. Thus, manipulation on more complex intermediates later in the synthesis is reduced to a minimum. Acetonide 10 or dimer 13 represent the key intermediates of this concept (Scheme 2). The whole sequence has been run on a kg scale with an overall yield of 52% (s. Scheme 5).     

Synthese von (+)-Abscisinsäure

Synthesis of (+)-Abscisic Acid . Starting from (4S)-4-hydroxy-2,6,6-trimethylcyclohex-2-enone ( 2 ), a short synthesis of the natural (+)-abscisic acid ((+)- 1 ) has been accomplished.     

‘Mixed’ β-peptides: A unique helical secondary structure in solution. Preliminary communication

β-Hexapeptides 1–5 and a β-dodecapeptide 6 with sequences containing two different types of β-amino acids (aliphatic proteinageous side chains in the 2- or in the 3-position) have been prepared. CD (Fig. 1) and NMR measurements indicate that, with one exception, the secondary structures formed by these new β-peptides differ from those of isomers studied previously. Detailed NMR analysis of the β-hexapeptide 5 (with alternating β²,β³-building blocks) and molecular-dynamics simulations have produced a minimum energy conformation (Fig. 2,b)which might be described as a novel irregular helix containing ten- and twelve-membered H-bonded rings. This demonstrates the great structural variability of β-peptides, since three different helical secondary structures have been discovered to date.     

Capillary column SFC instrumentation based on piston pumps with a programmable back-pressure regulator for on-line mixing of mobile phases

An alternative phase delivery system based on piston pumps and a back-pressure regulator has been developed for capillary column SFC. The chromatography is not affected by the fast piston pump refill. A homogeneous on-line mixing of binary phases with simultaneous pressure programming is easily accessible without any additional computing. Acceptable reproducibilities (< 3.5% RSD for external and < 2.0% RSD for internal standard methods) were found with mixtures of 2-propanol/CO₂ as mobile phases using UV detection and split ratios of 1:60 and 1:120. Variation and control of the split are easily done by simple flow rate volumetric changes.     

Tricyclic Pyridine Derivatives with High Affinity to the Central Benzodiazepine Receptor

Novel tricyclic heterocycles were prepared and evaluated for their affinity to the central benzodiazepine receptor. The most potent compounds with IC₅₀'s in the nanomolar range were; found among thienoquinolizines and benzo[a]quinolizines (cf. Tables 2–5). The central ring of the tricyclic ring system may be partially unsaturated (cf. Tables 2 and 4) or fully unsaturated (cf. Tables 3 and 5) without loss of the high affinity to the receptor. The position of the ester group in the pyridinone ring is crucial for good binding (cf. Tables 1 and 2). It may be replaced by a broad variety of functional groups, e.g. amides, alkyl carbamates, alkyl groups, and hydroxyalkyl groups (cf. Tables 2–5). In the benzo[a]quinolizines, shifting the halogen atom from C(10) to C(9) leads to complete loss of affinity to the benzodiazepine receptor (cf. Table 4).     

Imatinib metabolite profiling in parallel to imatinib quantification in plasma of treated patients using liquid chromatography-mass spectrometry

Besides affecting the systemic bioavailability of the parent drug, drug metabolizing enzymes (DMEs) may produce bioactive and/or toxic metabolites of clinical interest. We have investigated the capability to analyze simultaneously the parent drug and newly identified metabolites in patients' plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The anticancer drug, imatinib, was chosen as a model drug because it has opened a new area in cancer therapy and is given orally and chronically. In addition, resistance and rare but sometimes severe side effects have been reported with this therapy. The quantification of imatinib and the profiling of its metabolites in plasma were established following three steps: (1) set-up of a generic sample extraction and LC-MS/MS conditions, (2) metabolite identification by LC-MS/MS using either in vitro incubations performed with human liver microsomes (HLMs) or patient plasma samples, (3) the simultaneous determination of plasma levels of imatinib and 14 metabolites in the plasma samples of 38 patients. Partial or cross method validation has been done and revealed that precise determinations of metabolite levels can be performed whereas pure standards are not available. Preliminary results indicate that the disposition of imatinib and its metabolites is related to interindividual variables and that outlier metabolite profiles can be revealed. This article underscores that, in addition to usual therapeutic drug monitoring (TDM), LC-MS/MS methods can simultaneously record a complete drug metabolic profile enabling various correlation studies of clinical interest.     

Reliability of veterinary drug residue confirmation: High resolution mass spectrometry versus tandem mass spectrometry

Confirmation of suspected residues has been a long time domain of tandem triple quadrupole mass spectrometry (QqQ). The currently most widely used confirmation strategy relies on the use of two selected reaction monitoring signals (SRM). The details of this confirmation procedure are described in detail in the Commission Decision 93/256/EC (CD). On the other hand, high resolution mass spectrometry (HRMS) is nowadays increasingly used for trace analysis. Yet its utility for confirmatory purposes has not been well explored and utilized, since established confirmation strategies like the CD do not yet include rules for modern HRMS technologies.