Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy

A new series of nitro
analogues of the duocarmycins was prepared
and evaluated for hypoxia-selective anticancer activity. The compounds
incorporate 13 different amine-containing side chains designed to
bind in the minor groove of DNA while spanning a wide range of base
strength from pKa 9.64 to 5.24. The most
favorable in vitro properties were associated with strongly basic
side chains, but the greatest in vivo antitumor activity was found
for compounds containing a weakly basic morpholine. This applies to
single-agent activity and for activity in combination with irradiation
or chemotherapy (gemcitabine or docetaxel). In combination with a
single dose of γ irradiation 50 at 42 μmol/kg
eliminated detectable clonogens in some SiHa cervical carcinoma xenografts,
and in combination with gemcitabine using a well-tolerated multidose
schedule, the same compound caused regression of all treated A2780
ovarian tumor xenografts. In the latter experiment, three of seven
animals receiving the combination treatment were completely tumor
free at day 100.