Synthesis of casimiroin and optimization of its quinone reductase 2 and aromatase inhibitory activities.

An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogues has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.

Zapotin prevents mouse skin tumorigenesis during the stages of initiation and promotion.

BACKGROUND: Zapotin, a flavonoid associated with Casimiroa edulis, was isolated as part of a program to discover natural inhibitors of carcinogenesis. Zapote blanco, the fruit of Casimiroa edulis, is consumed in many parts of the world. Zapotin is a non-toxic inducer of cellular differentiation, apoptosis and cell cycle arrest with cultured HL-60 promyelocytic cells. MATERIALS AND METHODS: An efficient chemical synthesis for zapotin was devised. Using this synthetic material, activity was examined in the two-stage mouse skin carcinogenesis model. RESULTS: Topical zapotin significantly inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin tumorigenesis, using the anti-initiation and anti-promotion protocols. CONCLUSION: Encouraging results from previous and current in vivo studies warrant further investigation of the chemopreventive activity of zapotin.

Synthesis and biological evaluation of (+/-)-abyssinone II and its analogues as aromatase inhibitors for chemoprevention of breast cancer.

An efficient and economical synthesis of the naturally occurring aromatase inhibitor abyssinone II was performed. The synthesis features an optimized aromatic prenylation reaction in which an arylcopper intermediate is reacted with prenyl bromide to afford a key intermediate that was converted to a prenylated aromatic aldehyde. Condensation of the aldehyde with an o-hydroxyacetophenone under Claisen-Schmidt conditions afforded a chalcone that was deprotected and cyclized in the presence of sodium acetate in refluxing ethanol to afford (+/-)-abyssinone II. The synthesis proved to be versatile enough to provide an array of abyssinone II derivatives that were evaluated as aromatase inhibitors. Methylation of the 4'-hydroxyl group of (+/-)-abyssinone II resulted in a significant increase in aromatase inhibitory activity, and further smaller increases in activity resulted from the methylation of the 7-hydroxyl group and removal of the prenyl side chain. As a result of these structural changes, the most active flavanone of the series was 20 times more potent than (+/-)-abyssinone II (IC50 40.95 microM).

Synthesis and cancer chemopreventive activity of zapotin, a natural product from Casimiroa edulis.

An efficient method has been developed to synthesize zapotin (5,6,2',6'-tetramethoxyflavone), a component of the edible fruit Casimiroa edulis, on a multigram scale. The synthesis utilizes a regioselective C-acylation of a dilithium dianion derived from a substituted o-hydroxyactophenone to afford a beta-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)-induced ornithine decarboxylase (ODC) activity with human bladder carcinoma cells (T24 cells), and TPA-induced nuclear factor-kappa B (NF-kappaB) activity with human hepatocellular liver carcinoma cells (HepG2 cells). These data suggest that zapotin merits further investigation as a potential cancer chemopreventive agent.