Metal binding by pharmaceuticals. part 2. interactions of Ca(II), Cu(II), Fe(II), Mg(II), Mn(II) and Zn(II) with the intracellular hydrolysis products of the antitumour agent ICRF 159 and its inactive homologue ICRF 192

Abstract

Formation constants for the calcium(II), copper(II), iron(II), magnesium(II), manganese(II) and zinc(II) complexes ofdl-NN'-dicarboxamidomethyl-NN'-dicarboxymethyl-1,2-diaminopropane (ICRF 198) and the 1,2-diamino-butane homologue (ICRF 226) have been measured potentiometrically at 37°C andI=150 mmol dm⁻³ [NaCl]. The constants are used in computer simulation models to assess the relative avidity of these compounds for biologically essential metal ionsin vivo. It is shown that the agents interact similarly with all of the ions studied except those of zinc(II), which are particularly strongly chelated by the hydrolysis product of ICRF 192. This effect could be responsible for the difference in cytotoxicity exhibited by the antitumour agent ICRF 159 (Razoxane) and its inactive homologue ICRF 192. However, the mechanism through which this might occur remains unclear.