RESUMO
New prodrugs of daunorubicin, 1c, 1e and 2c, including a galactopyranosyl residue linked to the N-3' of the daunosaminyl moiety through substituted o- or p-benzyloxycarbonyl groups were synthesized. Their low cytotoxicity and high stability in plasma fulfil the conditions for antibody-directed enzyme prodrug therapy (ADEPT). Enzymatic hydrolysis using alpha-D-galactosidase gives rise to daunorubicin by subsequent self-elimination of the spacers. However, elimination clearly depends on the aromatic substitution pattern, as demonstrated especially by comparison with non-substituted analogues.
Assuntos
Daunorrubicina/análogos & derivados , Daunorrubicina/uso terapêutico , Terapia Enzimática , Imunotoxinas/química , Pró-Fármacos/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/toxicidade , Daunorrubicina/administração & dosagem , Estabilidade de Medicamentos , Humanos , Imunotoxinas/sangue , Imunotoxinas/toxicidade , Camundongos , Fenóis/sangue , Fenóis/síntese química , Fenóis/toxicidade , Pró-Fármacos/síntese química , Relação Estrutura-Atividade , alfa-Galactosidase/metabolismoRESUMO
Racemic 7-hydroxy-9-oxa-anthracyclinone (5a) has been synthetised in seven steps from quinizarin (6) and its resolution achieved after glycosylation with 3,4-di-O-acetyl-2-deoxy-L-fucose. Chiral pool syntheses of (8S)-8-hydroxymethyl-9-oxa-anthracyclinone (5b) and of (8S,10R) and (8S,10S)-8-hydroxymethyl-10-methyl-9-oxa-anthracyclinones (5c and 5d) have been achieved using (R)-2,3-O-isopropylideneglyceraldehyde (12) and leucoquinizarin (13) as starting materials. Glycosylation of aglycones 5b-5d by either 3,4-di-O-acetyl-2-deoxy-L-fucose or various 3-amino-2,3,6-trideoxy-L-hexoses yielded the corresponding anthracyclines. The synthetic glycosides do not show significant cytotoxic activity at a concentration of 1 microgram/ml against L 1210 cells.