posted on 1996-06-19, 00:00authored bySeung-Joo Lee, John M. Cassady, Laurence H. Hurley
Psorospermin is a DNA-reactive natural product isolated
from the roots of the tropical African plant
Psorospermum febrifugum that shows significant promise as an
antileukemic agent. Incubation of this antineoplastic
agent with DNA results in the production of sequence selective abasic
sites on the DNA. Using high-field NMR
and gel electrophoresis, the mechanism of covalent modification of DNA
and the mode of interaction with DNA are
determined. Psorospermin intercalates the DNA molecule,
positioning the tricyclic xanthone chromophore in an
orientation parallel to the adjacent base pairs. This places the
epoxide in the major groove, resulting in site-directed
electrophilic addition of the epoxide to N7 of guanine located to the
3‘ side of the site of DNA intercalation. It is
proposed in this study that the subsequent depurination of the
psorospermin−N7-guanine adduct is the source of
the
previously observed in vivo formation of abasic sites on the
DNA. Significantly, although the chemical structure
and mechanism of covalent modification of DNA are very similar to those
of the pluramycin class of agents, there
are distinct differences in the relative reactivities and sequence
selectivity between psorospermin and pluramycin-like compounds that may give rise to observed variances in biological
activity. Specifically, while psorospermin is
much less reactive than most of the pluramycins, it shows unique
selectivity for 5‘GG* sequences (the asterisk
designates the site of covalent modification), which is the least
reactive site for all of the pluramycins investigated
thus far. On the basis of the solution NMR structure of the
psorospermin−DNA covalent adduct, the underlying
structural differences that give rise to this lower reactivity and
different sequence specificities are proposed.