Eleven new polymeric carboxylic acids with widely different solubilities in water have been synthesized. The activities of these polymers against the ascitic sarcoma 180 tumor of mice and their acute toxicities in mice have been compared with molecular parameters of the polymers such as molecular weights, charge densities, and abilities to complex calcium and magnesium ions. The maximum effectiveness of these polymers against ascitic sarcoma 180 of mice is greatest for those polymers having fewer carboxyl groups ionized at pH 7. Toxicities are lower for polymers having more carboxyl groups ionized at pH 7.

Compounds having the basic structure N-(R)-substituted ring-substituted 4-iminocyclohexadienone have been synthesized and tested as antitumor agents against the ascitic sarcoma 180 tumor in Swiss mice. Among these compounds, the dimethylindoanilines [R = 4-(CH3)2NC6H4] are most stable in water at pH 7.0 and at 25 degrees C, the oximes (R = oh) are less stable, and the N-halo compounds (R = Br and Cl) are least stable. The N-halo derivatives have the highest redox potentials under the conditions used, the greatest effect against ascitic sarcoma 180 in Swiss mice, and the greatest acute toxicity when injected ip in the Swiss mice. Discriminant analysis of the results indicates that substituents with positive values of F and negative values of pi increase the antitumor activities, whereas those with positive values of sigma and R should lower the toxicity. The redox potential, a molecular parameter, is the best single variable for discriminating between the groups based on antitumor activities.

It has previously been found that naphthoquinones can potentiate the rate of hydrogen peroxide production by mitochondrial preparations of Trypanosoma brucei brucei and that organisms treated with naphthoquinones are more susceptible to lysis, especially in the presence of compounds such as heme, which promote the homolytic cleavage of hydrogen peroxide. We have evaluated the lytic effect of various N-substituted p-benzoquinone imines both in vitro and in vivo and have attempted to correlate their structure with trypanocidal activity using the Hansch approach. While none of the compounds tested proved to be active in vivo, all caused the lysis of trypanosomes in vitro. The parameters that correlated best with trypanocidal activity were the conditional redox potential, the lipophilicity of the substituent attached to the nitrogen atom and the number of active hydrogens on the quinonoid ring. These findings suggest two possible modes of action, which may in fact be related. Conjugate nucleophilic addition and/or oxidative damage could be responsible for lysis of the parasites. These same compounds were previously found to be active against the ascitic sarcoma 180 in mice. The strong correlation between antineoplastic activity in vivo and trypanocidal activity in vitro suggests a similar mode of action in both cases. Further studies aimed at developing a quinonelike compound that will be active against trypanosomes in vivo are now in progress.

ABSTRACT. The antitumor activities of t7 nitrogen analogs of 1, 4-benzoquinone, expressed in eight different ways, were subjected to discriminant analysis. Different methods of measuring the effectiveness of antitumor agents give different results. Methods based on dose levels such as the optimum dose or the lethal dose appear to be more useful in classifying compounds as antitumor agents than methods based on the maximum antitumor effect. A new index for antitumor activity involving the maximum antitumor effect, the optimum dose, and the therapeutic index, examined by discdminant analysis with substitutive parameters as discriminatory variables, can give valuable information for the design of new antitumor drugs.

Polymere Carbonsäuren auf Basis von nach üblichen Verfahren hergestellten Copolymeren der Acrylsäure (I)‐(III) werden als anionische Polymere hinsichtlich einer tumorhemmenden Wirkung untersucht.