Hypoxia-Selective Antitumor Agents. 5. Synthesis of Water-Soluble Nitroaniline Mustards with Selective Cytotoxicity for Hypoxic Mammalian Cells

Article abstract of DOI:10.1021/jm00095a018

Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine.However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E_1/2 ca. -600mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction.To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines.The N-<(N,N-dimethylamino)ethyl>carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the noncarboxamide compounds, were still low and little selectivity for hypoxic cells were observed.A series of carboxamides of 2,4-dinitroaniline mustard was also prepared.These compounds had reduction potentials in the desired range (E_1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells.The most selective compounds were 5--2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-<(N,N-dimethylamino)ethyl>carboxamide analogue.These showed selectivities of 60- to 70-fold for hypoxic UV4 cells.The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system.Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase).Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for the its higher hypoxic selectivity than that of 23.