Seven new [acronyculatins I–O (1–7)] and four known acetophenone monomers were isolated from a CH3OH/CH2Cl2 (1:1) extract (N089419) of Acronychia trifoliolata provided by the U.S. National Cancer Institute (NCI, Frederick, MD, USA). Their structures were characterized by using various NMR and HRMS techniques. Among the known compounds, the structure of acronyculatin B (8) was revised. Some of the isolated compounds were evaluated for antiproliferative activity against human cancer cell lines. While most of the tested compounds were not cytotoxic, acronyculatins I (1) and J (2) showed moderate antiproliferative activity.

Six acetophenone derivatives, acronyculatins I (1), J (2), K (3), L (4), N (5), and O (6), were recently isolated from Acronychia trifoliolata, and the structure of the known acronyculatin B (7) was revised. Because of the limited quantities of isolated products as well as their structure similarity, racemic acronyculatins I–L, N, O, and B (1–7) were synthesized to confirm their structures and to obtain sufficient material for biological evaluation. Trihydroxyacetophenone was converted to the target compounds by various sequences of hydroxy group protection, allylation or prenylation, and epoxidation followed by cyclization. C-Prenylations were carried out by direct addition of a prenyl group or through 1,3- or 3,3-sigmatropic rearrangement. The synthesized racemic compounds were evaluated in an anti-tumor-promoting assay using the Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds significantly inhibited EBV-EA activation. Especially, racemic acronyculatin I (1) displayed the most potent inhibitory effects, with an IC50 value of 7.3 μM.

The isolation of 12 secondary metabolites, including seven new acetophenone monomers, from the 50% CH 3 OH/CH 2 Cl 2 extract (N089419-L/6) of Acronychia trifoliolata was reported previously. In the present work, three new prenylated acetophenone dimers (1-3) and five known dimers (4-8) were isolated, and their structures were elucidated by using various NMR spectroscopic techniques and HRMS. Among the new dimers, an unprecedented 4-isobutyl-3 isopropyltetrahydro-2H-pyran ring was observed in the structure of 1. This study is the first to report the formation of a 2H-pyran ring between two prenylated acetophloroglucinols. Only four related dimers have been reported before, and they were formylated phloroglucinol dimers from the family Eucalypteae. Compounds 2 and 3 are acrovestone-like dimers, and the structure of 3 was confirmed by total synthesis. The evaluation of the antiproliferative activity of isolated and synthesized acrovestone-like dimers indicated that a double bond in the prenyl-like moiety as *