Nitro <i>seco</i> Analogues of the Duocarmycins
Containing Sulfonate Leaving Groups as Hypoxia-Activated Prodrugs
for Cancer Therapy
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Abstract
The synthesis of 19 (5-nitro-2,3-dihydro-1<i>H</i>-benzo[<i>e</i>]indol-1-yl)methyl sulfonate prodrugs containing
sulfonate
leaving groups and 7-substituted electron-withdrawing groups is reported.
These were designed to undergo hypoxia-selective metabolism to form
potent DNA minor groove-alkylating agents. Analogues <b>17</b> and <b>24</b>, containing the benzyl sulfonate leaving group
and a neutral DNA minor groove-binding side chain, displayed hypoxic
cytotoxicity ratios (HCRs) of >1000 in HT29 human cancer cells
in
vitro in an antiproliferative assay. Four analogues maintained large
HCRs across a panel of eight human cancer cell lines. In a clonogenic
assay, <b>19</b> showed an HCR of 4090 in HT29 cells. Ten soluble
phosphate preprodrugs were also prepared and evaluated in vivo, alone
and in combination with radiation in SiHa human tumor xenografts at
a nontoxic dose. Compounds <b>34</b> and <b>39</b> displayed
hypoxic log<sub>10</sub> cell kills (LCKs) of 1.78 and 2.71, respectively,
equivalent or superior activity to previously reported chloride or
bromide analogues, thus showing outstanding promise as hypoxia-activated
prodrugs