Structure-activity relationships in the acronycine and benzo[b]acronycine series: Role of the pyran ring

The pyranoacridone alkaloid acronycine (1), originally isolated from Acronychia baueri Schott (Rutaceae), has shown interesting properties against solid tumors. Significant improvements in terms of solubility and potency were obtained with derivatives modified in the pyran ring, such as diesters of cis-1,2-dihydroxy-1,2-dihydroacronycine (2) and cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine (3). Their mechanism of action implies alkylation of the 2-amino group of DNA guanine residues by the carbocation resulting from the elimination of the ester leaving group at position 1 of the drug.

In order to explore the structure-activity relationships in the acronycine series, simplified analogues of cis-1,2-diacetoxy-1,2-dihydroacronycine and cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine lacking the fused pyran ring, but possessing an acetoxymethyl leaving group at position 4 were prepared.

These compounds only displayed marginal antiproliferative activity compared to the parent compounds 2 and 3. In terms of structure-activity relationships, the presence of the angularly fused dimethylpyran ring appears as an indispensable structural requirement to observe significant cytotoxic activity [1].

References: 1. Do, Q. et al. (2008) Eur. J. Med. Chem. in press