Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications

摘要

Cytotoxic constituents of the terrestrial plant Bridelia ferruginea were isolated using bio activity -guided fractionation, which revealed the presence of the previously known deoxypodophyllotoxin (1), isopicrodeoxypodophyllotoxin (2), beta-peltatin (3), fl-peltatin-5-O-beta-D-glucopyranoside (3a), and the indole neoechinulin (4). As an extension of previous podophyllotoxin research, SAR studies were undertaken focused on 4-aza-podophyllotoxin structural modifications. A number of such derivatives were synthesized following modifications to the A and E rings. Such structural modifications with alkyl and 4-fluorobenzyl substituents at the 4-aza position provided the most potent cancer cell growth inhibitory activity (GI(50) 0.1 to 0.03 mu g/mL) against a panel of six human cancer cell lines and one murine dancer cell line. Several compounds corresponding to 4'-demethylated modifications were also synthesized and found to be significantly less potent.