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

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

  • J Nat Prod. 2016 Mar 25;79(3):507-18. doi: 10.1021/acs.jnatprod.5b00873.
George R Pettit 1 Justin D Searcy 1 Rui Tan 1 Gordon M Cragg 2 Noeleen Melody 1 John C Knight 1 Jean-Charles Chapuis 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Arizona State University , P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
  • 2 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.
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.

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