Synthesis and Cancer Chemopreventive Activity of Zapotin, a Natural Product from <em>Casimiroa edulis</em>

Arup Maiti

Muriel Cuendet

Tamara Kondratyuk

Vicki Croy

John Pezzuto

Mark Cushman

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, College of Pharmacy, Nursing and Health Sciences, and The Purdue Cancer Center, Purdue University, West Lafayette, IN 47907

*To whom correspondence should be addressed. Tel. 765-494-1465, Fax 765-494-6790, email ude.eudrup.ycamrahp@namhsuc

^{Contributed equally to this work.}

^{Current address: University of Hawaii at Hilo, College of Pharmacy, Hilo, Hawaii, 96720}

Abstract

An efficient method has been developed to synthesize zapotin (5,6,2′,6′-tetramethoxyflavone), a component of the edible fruit Casimiroa edulis, on multi-gram scale. The synthesis utilizes a regioselective C-acylation of a dilithium dianion derived from a substituted o-hydroxyactophenone to afford a β-diketone intermediate that can be cyclized to zapotin in good overall yield, thus avoiding the inefficient Baker-Venkataraman rearrangement pathway. Zapotin was found to induce both cell differentiation and apoptosis with cultured human promyelocytic leukemia cells (HL-60 cells). In addition, the compound inhibits 12-O-tetradecanoylphorbol 13-acetate (TPA^c)-induced ornithine decarboxylase (ODC) activity with human bladder carcinoma cells (T24 cells), and TPA-induced nuclear factor-kappa B (NF-κB) activity with human hepatocellular liver carcinoma cells (HepG2 cells). These data suggest that zapotin merits further investigation as a potential cancer chemopreventive agent.

Abstract

Footnotes

^{Abbreviations: TPA, 12-}O-tetradecanoylphorbol 13-acetate; ODC, Ornithine decarboxylase; T24 cells, Human bladder carcinoma cells; NF-κB, Nuclear factor-kappa B; HepG2 cells, Human hepatocellular liver carcinoma cells, HL-60 cells, Promyelocytic leukemia cells; DAPI, 4′,6-Diamidino-2-phenylindole; LiHMDS, Lithium hexamethyldisilazide; BrdU, 5-bromo-2-deoxyuridine.

Supporting Information Available. ^{H NMR,}^{C NMR and elemental analyses for compound}12 and zapotin (1). This material is available free of charge via the Internet at http://pubs.acs.org.

Footnotes

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