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
Posted on 2017-06-22 - 20:49
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.
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Tercel, Moana; Lee, Ho H.; Mehta, Sunali Y.; Youte Tendoung, Jean-Jacques; Bai, Sally Y.; Liyanage, H. D. Sarath; et al. (2017). 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. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.7b00563
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AUTHORS (7)
MT
Moana Tercel
HL
Ho H. Lee
SM
Sunali Y. Mehta
JY
Jean-Jacques Youte Tendoung
SB
Sally Y. Bai
HL
H. D. Sarath Liyanage
FP
Frederik B. Pruijn
KEYWORDS
combination treatmentp KBasic Side Chaincompoundside chainslatter experimenthypoxia-selective anticancer activitytumor xenograftsHypoxia-Selective Nitro Analoguesbase strengthamine-containing side chainsγ irradiation 50carcinoma xenograftsDNAvivo antitumor activitywell-tolerated multidose schedulegemcitabineSubstantial Anticancer Activitysingle-agent activitynitro analogues