Synthesis, cytotoxic activity and mechanism of action of new Psorospermin-Acronycine analogs

Psorospermin 1 is a natural dihydrofuroxanthone wich was first isolated by Kupchan [1] in 1980 from barks and roots of Psorospermum febrifugum Sprach (Guttiferae). Its mechanism of action implies covalent binding to the N-7 position of the guanine units in DNA major groove [2]. In contrast, acronycine derivatives developed in our laboratory, exemplified by S-23906 which recently underwent phase I clinical trials, were shown to alkylate the 2-amino group of DNA guanine residues in the minor groove [3]. In a continuation of our studies on the structure activity relationships in the acronycine and psorospermin series, we present here the synthesis and the biological properties of new epoxides in the 11H-furo[2,3-c]acridin-6-one and 13H-benzo[b]furo[3,2-h]acridin-6-one series, with the aim of determining the influence of the acidone or xanthone basic core on the one hand, and the fused pyran or furan unit on the other hand, on the cytotoxic properties and DNA-alkylation mechanism.

The presence of an epoxy substitution on the furan ring appears as an important structural requirement to observe a marked cytotoxic activity against L1210 and KB-3–1 cell lines. In contrast with the acronycine derivatives, the new analogs were shown to alkylate the N-7 position of the DNA guanine residues.

References: 1. Kupchan, SM. et al. (1980)J. Nat.Prod. 43:296–301.

2. Cassady, JM. et al. (1996)J. Am. Chem. Soc. 118:5553–5561.

3. Tillequin, F. et al. (2003)J. Med. Chem. 46:3072–3082.