title: Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications.
abstract: Cytotoxic constituents of the terrestrial plant Bridelia ferruginea were isolated using bioactivity-guided fractionation, which revealed the presence of the previously known deoxypodophyllotoxin (1), isopicrodeoxypodophyllotoxin (2), β-peltatin (3), β-peltatin-5-O-β-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 (GI50 0.1 to <0.03 μg/mL) against a panel of six human cancer cell lines and one murine cancer cell line. Several compounds corresponding to 4'-demethylated modifications were also synthesized and found to be significantly less potent.
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: George R
authors.initials: GR
authors.lastname: Pettit
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Searcy
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Tan
authors.affiliation: Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute , P.O. Box B, Frederick, Maryland 21702-1201, United States.
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Cragg
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Noeleen
authors.initials: N
authors.lastname: Melody
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Chapuis
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004365:Drugs, Chinese Herbal; D019665:Euphorbiaceae / Q000737:chemistry*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000609828:4-aza-podophyllotoxin; D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; C014451:deoxypodophyllotoxin; D011034:Podophyllotoxin