Synthesis, cytotoxic activity, and DNA binding properties of antitumor cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine cinnamoyl esters

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 cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine (2). Diacetate 2, has been developed under the code S23906–1 in phase I clinical trials. Its 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.

Monoester at position 2 (3), also exhibit cytotoxic and antitumor activity, despite the lack of leaving group at the benzylic position 1, due to a spontaneous transesterification process, leading to isomeric cis-monoester at position 1.

In this context, cinnamoyl esters appear as good drug candidates able to present a better stability toward hydrolytic processes. We describe here the synthesis of monocinnamoyl esters at position 2 (4) and their acetyl derivatives at position 1 (5) and their biological evaluation.

As expected, the cinnamoyl esters 4 as well as their acetyl counterparts 5 displayed significant cytotoxic and antitumoral activities. The most active compounds were about 20 to 30-fold more potent than the diacetate 2 and the monoacetate 3 in vitro but only two-fold more potent than the reference S-23906–1 (2) in vivo.