BIOCHEMICAL AND CHEMICAL CHARACTERIZATION OF PHENYLGLYOXAL BIS(GUANYLHYDRAZONE), AN AROMATIC ANALOG OF MITOGUAZONE

Since little has been known about the properties of aromatic analogues of the antineoplastic agent methylglyoxal bis(guanylhydrazone) (MGBG) , an investigation was performed on phenylglyoxal bis(guanylhydrazone) (PhGBG). PhGBG competitively inhibited yeast adenosylmethionine decar boxylase (AdoMetDC) with a K-i of 65 mu M. As compared to MGBG (K-i 0. 23 mu M), PhGBG is a much weaker inhibitor, being even weaker than the unsubstituted congener glyoxal bis(guanylhydrazone) (GBG, K-i 18 mu M ). PhGBG inhibited porcine kidney diamine oxidase (DAO) non-competitiv ely, being a more potent inhibitor (K-i 0.12 mu M) than GBG (K-i 0.17 mu M) or MGBG (K-i 0.33 mu M). Thus, PhGBG has an unfavourably high ra tio of K-i(AdoMetDC)/K-i(DAO) for potential use for selectively inhibi ting polyamine biosynthesis. This does not exclude the possibility tha t PhGBG or other aromatic congeners might have therapeutic value since the corresponding ratio of the antileukaemic congeners GBG and MGBG i s also high as compared to many aliphatic non-antileukaemic analogues. The pK(a1) and pK(a2) values of PhGBG dication were found to be 6.39 +/- 0.92 and 8.64 +/- 0.02 respectively, their difference being distin ctly larger than in the case of GBG or its C-alkylated analogues. This may result from decreased stability of the dication form, caused by t he resonance effect or possibly by the inductive effect of the phenyl group. The species distribution of PhGBG (proportion of free base 5.5% , predominant species the monocation) at 37 degrees C resembles that o f GBG and MGBG but is clearly different from that of non-antileukaemic C-alkylated analogues. These similarities suggest that PhGBG and its derivatives may be worth antitumour screening. Depending on the condit ions used in the crystallization, three different types of crystals of PhGBG sulphate were obtained. Crystallography indicated that, in two of the types, the crystal consisted exclusively of the anti-anti isome r, i.e. the same isomer as has been observed in the case of GBG and it s C-alkylated congeners. One crystal type, however, consisted of a dif ferent geometrical isomer (anti-syn), suggesting that PhGBG may isomer ize more easily than its aliphatic analogues. Previous concepts on the isomerism of GBG and C-alkylated bis(guanylhydrazones) thus cannot be generalized to aromatic congeners. A theory based on resonance, induc tive and hyperconjugative effects and electron transfers is presented that is capable of explaining the formation of the two geometrical iso mers of PhGBG that were experimentally observed. A similar theory, bas ed on hyperconjugation of C-F bonds, is presented that is capable of e xplaining the previous finding of the formation of the anti-syn isomer of trifluoromethylglyoxal bis(guanylhydrazone) (CF(3)GBG). Like that of CF(3)GBG, the anti-syn isomer of the PhGBG dication is stabilized b y an internal hydrogen bond. The lack of structural rigidity may affec t the biological properties of PhGBG, e.g. its ability to inhibit AdoM etDC.