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DOI: 10.1055/s-2007-987340
First Total Synthesis of Protoapigenone and its Analogs as Potent Cytotoxic Agents
A natural occurring flavonoid, protoapigenone, was isolated from the fern Thelypteris torresiana for the first time in 2005 [1]. This compound showed significant cytotoxic activity against five human cancer cell lines in the literature and had potential anti-tumor effects in an animal study [2]. In order to explore structure-activity relationships, identify additional active compounds, and investigate the mechanism of action, the first total synthesis of protoapigenone was achieved. By using hypervalent iodine reagent oxidation [3], 9 para-quinol analogs were also synthesized.
All newly synthesized compounds and related intermediates were evaluated for in vitro cytotoxic activity. The result showed that these compounds possessed obvious cytotoxicity against five human cancer cell lines, HepG2, Hep3B, MDA-MB-231, MCF-7 and A549. Among them, 5,7-dimethoxy protoapigenone showed enhanced and notable activity against four cell lines (Hep3B, MDA-MB-231, MCF-7 and A549) with IC50 values of 0.17–0.40µg/mL. 7-Methoxy protoapigenone, showed 2.1–13.7 fold greater cytotoxicity against all five tested cancer cell lines than parent compound. Furthermore, changing the A-ring from phenyl to naphthyl remarkably enhanced the activity. Analog 3-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)-1H-benzo[f]chromen-1-one strongly inhibited Hep3B cell growth with an IC50 value of 0.09µg/mL and was more potent than the positive control doxorubicin against this cell line.
Acknowledgements: Grants CA 17625 from National Cancer Institute, National Science Council, Taiwan.
References: [1] Lin A.-S. et al. (2005) Planta Med. 71: 867–870. [2] Unpublished data. [3] Wipf P. et al. (1994) J. Am. Chem. Soc. 116: 11678–11688.