H. Elo et al., BIOCHEMICAL AND CHEMICAL CHARACTERIZATION OF PHENYLGLYOXAL BIS(GUANYLHYDRAZONE), AN AROMATIC ANALOG OF MITOGUAZONE, Anti-cancer drug design, 11(7), 1996, pp. 493-508
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.