Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin.
Bioorg Chem
; 125: 105915, 2022 08.
Article
in En
| MEDLINE
| ID: mdl-35660840
ABSTRACT
To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,ß-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ovarian Neoplasms
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Bioorg Chem
Year:
2022
Document type:
Article