Antitumor Potential of the Isoflavonoids (+)- and (−)-2,3,9-Trimethoxypterocarpan: Mechanism-of-Action Studies

Synthetically
derived samples of (+)-(6aS,11aS)-2,3,9-trimethoxypterocarpan [(+)-1] and
its enantiomer [(−)-1], both of which are examples
of naturally occurring isoflavonoids, were evaluated, together with
the corresponding racemate, as cytotoxic agents against the HL-60,
HCT-116, OVCAR-8, and SF-295 tumor cell lines. As a result it was
established that compound (+)-1 was particularly active
with OVCAR-8 cells being the most sensitive and responding in a dose-dependent
manner. A study of cell viability and drug-induced morphological changes
revealed the compound causes cell death through a mechanism characteristic
of apoptosis. Finally, a computational study of the interactions of
compound (+)-1 and (S)-monastrol, an
established, synthetically derived, potent, and cell-permeant inhibitor
of mitosis, with the kinesin-type protein Eg5 revealed that both bind
to this receptor in a similar manner. Significantly, compound (+)-1 binds with greater affinity, an effect attributed to the
presence of the associated methoxy groups.