POTENTIAL ANTI-TUMOR AGENTS .31. QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE ANTI-LEUKEMIC BIS(GUANYLHYDRAZONES)

Certain L1210-active bis(guanylhydrazones) have structural and biological properties in common with the DNA minor groove binding, antileukemic, bisquaternary ammonium heterocycles. Monitoring of the DNA binding of the bis(guanylhydrazones), by fluorimetric quantitation of drug displacement of DNA-bound ethidium, shows that, like the bisquaternary salts, these agents bind more strongly to poly[d(A-T)] than poly[d(G-C)]. The drug concentrations necessary to inhibit L1210 DNA-dependent DNA polymerase in vitro by 50% (IC50) are linearly related to measures of drug-DNA binding with no preference for a particular primary sequence of DNA being evident. Mammalian toxicity of the bis(guanylhydrazones) is effectively modeled by a regression equation containing binomial terms in Rm values, used as a measure of agent lipophilic-hydrophilic balance, and the logarithms of the IC50 values. © 1979, American Chemical Society. All rights reserved.