Psorospermin, A New Antileukemic Xanthone From Psorospermum febrifugum

Abstract

An ethanolic extract of Psorospermum febrifugum was fractionated with antileukemic activity in vivo in the P388 lymphocytic leukemia in mice and in vitro in the KB cell culture system used as a guide. The new antileukemic xanthone psorospermin 1 was isolated, and its structure was elucidated. The chlorohydrin of O-methylpsorospermin 2 was also isolated after treatment of the fraction containing psorospermin chlorohydrin 6 with diazomethane. Psorospermin 1 was demonstrated to have significant antitumor activity in the P388 in vivo system as well as cytotoxicity against the KB in vitro system.

Topoisomerase II Site-directed Alkylation of DNA by Psorospermin and Its Effect on Topoisomerase II-mediated DNA Cleavage

“…2, oligo I) was enhanced more than 25-fold in the presence of topoisomerase II. 2 It was proposed that a topoisomerase II-mediated structural distortion in DNA creates the high-affinity DNA binding site for psorospermin. 2 However, it was not determined at which stage during the topoisomerase II catalytic cycle this proposed distortion takes place.…”

“…In the absence of drug, the intensity of the DNA cleavage induced by topoisomerase II is much less at site B than at site A (see below). 2 To examine the psorospermin alkylation in the presence of topoisomerase II, a strand breakage assay was used in which the 5Ј end-labeled DNA was incubated with Drosophila topoisomerase II to form the topoisomerase II-DNA complex. Psorospermin was then added to the reaction mixture followed by piperidine-heat treatment to generate the strand breakage products from the psorospermin-(N-7-guanine) DNA adduct (3).…”

“…2 Because the magnitude of this enhancement is pH-dependent, experiments were designed to determine the effect of pH on the psorosperminstimulated DNA cleavage produced by topoisomerase II. In the absence of drug, the topoisomerase II-DNA cleavage is much less at site B than at site A, regardless of the pH that was used (Fig.…”

“…Furthermore, although topoisomerase I and II can form cross-links to DNA in the presence of psorospermin, it was suggested that these cross-links are not specific (5). However, we have recently demonstrated that psorospermin alkylation at specific sites on DNA was greatly enhanced in the presence of topoisomerase II, 2 indicating that the antitumor activity of psorospermin might be related to its specific interaction with the topoisomerase II-DNA complex.…”

“…1), a natural product isolated from the roots and stem bark of the African plant Psorospermum febrifugum (1,2), has been shown to intercalate into the DNA helix and to covalently modify guanine at the N-7 position in the major groove through an epoxide-mediated electrophilic attack (3). It is active against drug-resistant human leukemia lines and AIDS-related lymphoma.…”