TY  - JOUR
A1  - Hartung, Andreas
A1  - Seufert, Florian
A1  - Berges, Carsten
A1  - Gessner, Viktoria H.
A1  - Holzgrabe, Ulrike
T1  - One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties
JF  - Molecules
N2  - The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic alpha-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with beta-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses.
KW  - multicomponent Ugi-type reaction
KW  - intramolecular Michael addition
KW  - strategy
KW  - derivates
KW  - diketopiperazines
KW  - chemistry
KW  - T cell
KW  - 2,5-diketopiperazines
KW  - anti-proliferative effects
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130423
VL  - 17
IS  - 12
ER  - 
TY  - JOUR
A1  - Wohlfart, Jonas
A1  - Holzgrabe, Ulrike
T1  - Analysis of histamine and sisomicin in gentamicin: search for the causative agents of adverse effects
JF  - Archiv der Pharmazie
N2  - In 1998, the aminoglycoside antibiotic gentamicin sulfate caused several cases of deaths in the United States, after the switch from twice- to once-daily application. Endotoxins were discussed as the cause for the adverse effects and sisomicin was identified as the lead impurity; batches containing sisomicin were contaminated with more impurities and were responsible for the fatalities. In 2016, anaphylactic reactions in horses, and later in humans with one fatality, were observed after application of gentamicin sulfate contaminated with histamine. To determine whether histamine was responsible for the 1990s death cases as well, histamine was quantified by means of liquid chromatography–tandem mass spectrometry (LC-MS/MS) in 30 samples of gentamicin sulfate analyzed in previous studies. Furthermore, a relative quantification of sisomicin was performed to check for a correlation between histamine and the lead impurity. A maximum amount of 11.52 ppm histamine was detected, which is below the limit for anaphylactic reactions of 16 ppm, and no correlation of the two impurities was observed. However, the European Medicines Agency recommends a stricter limit with regard to the maximum single dose of gentamicin sulfate to reach a greater gap between the maximum histamine exposition of 4.3 µg and the quantity known to cause hypotension of 7 µg. The low amounts of histamine and the fact that there is no connection with the contamination with sisomicin showed that histamine was not the cause for the death cases in the United States in 1998, and endotoxins remain the most probable explanation.
KW  - chemistry
KW  - sisomicin
KW  - drug impurities
KW  - gentamicin sulfate
KW  - histamine
KW  - LC-MS/MS
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256596
VL  - 354
IS  - 12
ER  -