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Degradation and intracellular phosphorylation of showdomycin
Abstract:
The anti-tumor agent showdomycin is degraded in the presence of 0.05 M NH4HCO3 (pH 8.0) to a compound which carries a negatively charged group. Together with previous data (Darnall et al., 1967) it is suggested that ammonia causes a basic hydrolysis of the maleimide moiety under formation of a maleic acid-like compound. During this modification the C-glycosidic bond is not split. Intracellularly, in mouse lymphoma cells (L5178y), showdomycin is phosphorylated to showdomycintriphosphate, via the mono- and diphosphate stage.
Insights
The anti-tumor drug showdomycin degrades into a negatively charged compound via basic hydrolysis. Intracellularly, showdomycin is phosphorylated to showdomycintriphosphate in mouse lymphoma cells.
Area of Science:
- Biochemistry
- Pharmacology
- Organic Chemistry
Background:
- Showdomycin is an anti-tumor agent.
- Understanding showdomycin's degradation pathways is crucial for its therapeutic application.
- Previous studies (Darnall et al., 1967) indicated potential reactivity with ammonia.
Purpose of the Study:
- To investigate the degradation products of showdomycin under specific conditions.
- To elucidate the mechanism of showdomycin degradation.
- To explore the intracellular metabolic fate of showdomycin.
Main Methods:
- Incubation of showdomycin with 0.05 M NH4HCO3 at pH 8.0.
- Analysis of degradation products to identify chemical modifications.
- Intracellular studies using mouse lymphoma cells (L5178y) to track phosphorylation.
Main Results:
- Showdomycin degrades to a compound with a negative charge.
- Ammonia induces basic hydrolysis of the maleimide moiety, forming a maleic acid-like compound.
- The C-glycosidic bond remains intact during degradation.
- Intracellularly, showdomycin is converted to showdomycintriphosphate through mono- and diphosphate intermediates.
Conclusions:
- Showdomycin undergoes chemical modification in the presence of ammonia, yielding a negatively charged derivative.
- The maleimide ring is susceptible to basic hydrolysis, but the C-glycosidic bond is stable.
- Showdomycin is metabolically activated intracellularly via phosphorylation in mouse lymphoma cells.