4533-39-5Relevant academic research and scientific papers
Hypoxia-Selective Antitumor Agents. 4. Relationships between Structure, Physicochemical Properties, and Hypoxia-Selective Cytotoxicity for Nitracrine Analogues with Varying Side Chains: The "Iminoacridan Hypothesis"
Denny, William A.,Atwell, Graham J.,Anderson, Robert F.,Wilson, William R.
, p. 1288 - 1295 (2007/10/02)
The nitroacridine derivative nitracrine is a potent hypoxia-selective cytotoxin for mammalian cells in culture.In an attempt to modulate the degree of hypoxia selectivity among this class of compounds, we have studied a series of side-chain analogues of nitracrine.Both the electronic and steric properties of the side chain are shown to be important in determining the hypoxia selectivity of the compounds, by controlling the degree of aminoacridine/iminoacridan tautomerism.Studies with the repair-defective Chinese hamster cell line UV4 indicate that the cytotoxicity ofall the compounds is due to nitro group reduction and subsequent macromolecular adduct formation.However, compounds such as the 9-amino derivative, which exist totally as the aminoacridine tautomer, form much less lethal lesions than the 9-alkylamino derivatives, which exist to varying degrees in the iminoacridan conformation.For the whole set of compounds, the degree of hypoxia-selective cytotoxicity correlates well with the proportion of iminoacridan tautomer present.
Hypoxia-selective antitumor agents. 1. Relationships between structure, redox properties and hypoxia-selective cytotoxicity for 4-substituted derivatives of nitracrine
Wilson,Anderson,Denny
, p. 23 - 30 (2007/10/02)
The nitroacridine derivative 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) is selectively cytotoxic to hypoxic tumor cells in culture. However, the compound undergoes reductive metabolism too rapidly, with the reduction not being sufficiently inhibited by molecular oxygen in aerobic tissues, for it to demonstrate the same activity in vivo. In a search for derivatives with lower reduction potentials, we have synthesized and evaluated a series of derivatives bearing 4-substituents with a wide range of electronic properties. The one-electron reduction potentials (E(1)) of these compounds, when compared under conditions of equivalent ionization, were highly correlated with σ(p) values. However, at pH 7 the influence of substituent electronic properties was modified by prototropic equilibria, with the basic nature of the acridine limiting the extent to which ring substituent electronic effects can be used to modulate reduction potential of the 1-nitro group. Nevertheless, comparison of the kinetics of the killing of AA8 cells under hypoxia suggests that some metabolic stabilization of the compounds can be achieved by the use of electron-donating substituents, with such compounds retaining the hypoxia-selective toxicity of nitracrine in cell culture. However, the 4-substituted nitracrines show no clear relationship between E(1) and cytotoxic potency, in distinct contrast to simpler nitroheterocycles such as nitroimidazoles.
