Mustards, aniline

On the other hand, it is all too easy to find QSARs that fail one or other of the statistical criteria, or have other faults. An early example, involving the tumor-promoting ability of aniline mustard drugs, was [46] ... 

Leo A, Panthananickal A, Hansch C, Theiss J, Shimkin M, Andrews AW. A comparison of mutagenic and carcinogenic activities of aniline mustards. J Med Chem 1981 24 859-64. 

Prakash, A. S. Denny, W. A. Gourdie, T. A. Valu, K. K. Woodgate, P. D. Wakelin, L. P. G. DNA-directed alkylating ligands as potential antitumor agents sequence specificity of alkylation by intercalating aniline mustards. Biochemistry 1990, 29, 9799-9807. 

M. P. Gamcsik, K. K. Millis, T. G. Hamill, Kinetics of the Conjugation of Aniline Mustards with Glutathione and Thiosulfate , Chem.-Biol. Interact. 1997, 105, 35 - 52. 

Lewis, D.F.V., Molecular orbital calculations on tumor-inhibitory aniline mustards QSARs, Xenobiotica, 19, 243-251, 1989. 

Hansch, C., Telzer, B.R. and Zhang, L., Comparative QSAR in toxicology examples from teratology and cancer-chemotherapy of aniline mustards, Crit. Rev. Toxicol., 25, 67-89, 1995b. 

Sunters, A., Springer, C. J., Bagshawe, K. D., Souhami, R. L., and Hartley, J. A. (1992) The cytotoxicity, DNA crosslinking ability and DNA sequence selectivity of the aniline mustards melphalan, chlorambucil and 4-[bis(2-chloroethyl) aminojbenzoic acid. Biochem. Pharmacol. 44, 59-64. 

Cb 2Cr Cb + 2e NH2OH, phenol, aniline, mustard gas, mercaptans, 8-hydroxyquinoline, olefins As(III), P, styrene, fatty acids... 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Aniline Mustard. N,N-Bis(2-ckIoroethyl)benzen-amine A, N-6is (2-cftloroethyl)aniline phenylhis[2-chlOrO-... 

Quantitative Structure—Activity Relationships for the Cytotoxicity of Substituted Aniline Mustards in Tissue Culture... 

The stabilities and aerobic cytotoxicities (growth inhibition and effects on clonogenicity) of substituted aniline mustards against mammalian tumor ceils have been determined in tissue culture. 

The equations can be used to compute the maximum possible hypoxia selectivity of nitro-substituted aniline mustards. The 4-NOj compound does show hypoxia-selectivity (although at a much lower level than predicted), suggesting this approach to the design of hypoxia-selective antitumor agents is valid. 

It is well-established that the reactivity of aromatic nitrogen mustards in hydrolysis reactions correlates positively with the degree of electron release to the nitrogen (7). The rate constants for alkaline hydrolysis of a series of aniline mustards correlate well with a, as shown by Equation 1 (equation 23 of ref. 8). 

Finally, several QSAR studies (8,10,11) have shown that the acute toxicity and antitumor potency of substituted aniline mustards in vivo are also dominated by the electronic properties of substituent groups, although additional factors such as drug lipophilicity play a role in these systems. For example, the potencies (dose of drug required to provide an increase in lifespan or 25%) or a series of compounds against the B-16 melanoma in mice were best fitted by Equation 4 (equation 8 of ref. JJ). 

This similar dependence of in vivo potency and mustard reactivity on substituent electronic properties (cf Equations I and 4) has been cited (8) as evidence that the biological activity of these compounds is directly due to the rate at which they alkylate cellular DNA. However, in complex in vivo systems the possible roles of drug transport and metabolism as well as DNA repair have also to be considered. Surprisingly, there is virtually no quantitative data available on the cytotoxicity of substituted aniline mustards in mammalian cell culture systems, where the effects of substituent electronic effects on cytotoxicity and stability can be examined in the... 

We report here a QSAR study of the in vitro cytotoxicity of simple substituted aniline mustards, as part of a programme (5) directed towards the rational design of nitrophenyl mustards as hypoxia-selective agents. In order to study the effects of substituent groups, a carefully-selected set of derivatives... 

Table I. Physicochemical and Biological Data for Substituted Aniline Mustards...

The slope of the line (1.99) shows there is a very similar dependence of halflife in culture medium on substituent electronic properties (chemical hydrolysis of substituted aniline mustards (Equation 1 above). 

DENNY ETAL. CytoUmcity of Aniline Mustards in Tissue Culturt... 

The equations describing both the cytotoxicities and the alkylating abilities of substituted aniline chloromustards have similar slopes, suggesting that these compounds express their cytotoxicity primarily by alkylation. It is evident that the critical biological alkylation site is DNA, and that cytotoxicity is due to formation of DNA interstrand crosslinks, since the UV4 mutant defective in repair of these lesions (J4) shows marked hypersensitivity to the aniline mustards. 

While the majority of the aniline mustards showed no hypoxia-selective cytotoxicity in the growth inhibition assay (Table 1), the corresponding 4-NOj and 3-NOj compounds (3 and 4) were more toxic to UV4 cells under hypoxic conditions, with the 4-NOj derivative showing a toxicity ratio of 3.2 (Table... 

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