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Substituent Effects on the Coordination Chemistry of Metal-Binding Pharmacophores
A combination
of XAS, UV–vis, NMR, and EPR was used to examine
the binding of a series of α-hydroxythiones to CoCA. All three
appear to bind preferentially in their neutral, protonated forms.
Two of the three clearly bind in a monodentate fashion, through the
thione sulfur alone. Thiomaltol (TM) appears to show some orientational
preference, on the basis of the NMR, while it appears that thiopyromeconic
acid (TPMA) retains rotational freedom. In contrast, allothiomaltol
(ATM), after initially binding in its neutral form, presumably through
the thione sulfur, forms a final complex that is five-coordinate via
bidentate coordination of ATM. On the basis of optical titrations,
we speculate that this may be due to the lower initial p<i>K</i><sub>a</sub> of ATM (8.3) relative to those of TM (9.0) and TPMA
(9.5). Binding through the thione is shown to reduce the hydroxyl
p<i>K</i><sub>a</sub> by ∼0.7 pH unit on metal binding,
bringing only ATM’s p<i>K</i><sub>a</sub> close to
the pH of the experiment, facilitating deprotonation and subsequent
coordination of the hydroxyl. The data predict the presence of a solvent-exchangeable
proton on TM and TPMA, and Q-band 2-pulse ESEEM experiments on CoCA
+ TM suggest that the proton is present. ESE-detected EPR also showed
a surprising frequency dependence, giving only a subset of the expected
resonances at X-band