Cl-958,
PD 121373, and
PD 114595 belong to a new class of
DNA complexers, substituted 2H-[1]benzothiopyrano[4,3,2-cd]
indazoles, and are being further developed as
antitumor drugs based on their curative properties against murine solid
tumor models. The biochemical effects of these drugs on
L1210 leukemia cells and their interaction with
DNA were studied and compared to clinically used
intercalators. The benzothiopyranoindazoles bound to
DNA with a relatively high affinity, having intrinsic association constants of between 3 and 4 x 10(5) M-1. Based on viscosity measurements, the mode of
DNA binding appears to be through intercalation. Unwinding angles were calculated to be approximately 18 degrees. The benzothiopyranoindazoles were potent inhibitors of
nucleic acid synthesis, reducing both
DNA and
RNA synthesis to the same extent at similar concentrations. Like other known
intercalators, these compounds produced
DNA single- and double-strand breaks in a time- and concentration-dependent manner in L1210 cells. Between one and two
DNA strand breaks were formed per
protein-strand crosslink. Repair of these DNA lesions after the
drug was removed from the cells was either very slow or did not occur at all for at least 2 hr. Finally, since the high incidence of
cardiotoxicity associated with the administration of
anthracyclines has been related to the formation of
reactive oxygen species, the ability of the benzothiopyranoindazoles to augment
superoxide dismutase-sensitive oxygen consumption was observed in a rat liver microsomal system. These compounds produced less than 5% of the activity in this assay that
doxorubicin produced.