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Bioactive Annonaceous acetogenins have been isolated from the EtOH extract of the bark of Xylopia aromatica by bioactivity-directed fractionation using lethality to brine shrimp. These acetogenins include xylopianin [1 , xylopiacin [2], and xylomaticin [3], which are three new mono-tetrahydrofuran ring type acetogenins, in addition to the known compounds, annomontacin, gigantetronenin, gigantetrocin A, and annonacin. Compounds 1 and 2 are unusual in having hydroxylation at C-8; 3 has the same functionalities as annonacin but with 37 carbons instead of 35 carbons. The structures were elucidated by spectral analysis of the parent compounds and/or simple chemical derivatives. These acetogenins showed cytotoxicities, comparable to adriamycin, against three human solid tumor cell lines.

Asimicin and a new cytotoxic Annonaceous acetogenin, venezenin [1], were isolated from the bark of Xylopia aromatica by bioactivity-directed fractionation using lethality to brine shrimp. Compound 1 represents an unusual type of C37 Annonaceous acetogenin, lacking either tetrahydrofuran (THF) or epoxide rings and possessing a double bond located two methylenes away from a vicinal diol in the hydrocarbon chain. The structure of 1 was elucidated by 1H- and 13C-nmr, COSY, single-relayed COSY, and by HMBC techniques, and derivatization. Annomontacin 10-one [6] and 18/21-cis-annomontacin-10-one [7], two semi-synthetic mono-THF acetogenins were prepared from 1. These acetogenins showed cytotoxicity, comparable or superior to adriamycin, against three human solid tumor cell lines. Reduction of the 10-keto of 1 to the racemic OH-10 derivative enhanced the bioactivity, as did the conversion of 1 to 6 and 7. Venezenin [1], like other Annonaceous acetogenins, showed inhibition of oxygen uptake by rat liver mitochondria and demonstrated that the THF ring may not be essential to this mode of action.

The Annonaceous acetogenins represent a class of compounds with diverse bioactivities, including promising cytotoxicites. These are due, at least in part, to inhibition of complex I in the oxidative phosphorylation pathway in mitochondria. Fourteen Annonaceous acetogenins were tested in a rat liver mitochondrial oxygen uptake assay to probe additional structure-activity relationships. In this subcellular assay, the activity of non-adjacent bis-THF ring acetogenins depends on the distance between the two THF rings; the activity decreases to that of a mono-THF ring acetogenin if the distance is too long. When one THF ring is replaced with a tetrahydropyran ring, the activity remains comparable. The configuration of the THF ring, in mono ring compounds, seems to be more important than stereochemical differences in the rings of adjacent bis-THF ring compounds. Bullatacin, an adjacent bis-THF ring acetogenin, was used as a standard compound in every run to normalize the data.

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