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Probing Imidazotetrazine Prodrug Activation Mechanisms
Moody, Catherine L. Ahmad, Leena Ashour, Ahmed Wheelhouse, Richard T.
Moody, Catherine L.
Ahmad, Leena
Ashour, Ahmed
Wheelhouse, Richard T.
Publication Date
2017
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© 2017 The Authors. Published by MDPI. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0)
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Abstract
The archetypal prodrug of the imidazotetrazine class is the anticancer agent temozolomide (TMZ).
The prodrug activation kinetics of TMZ show an unusual pH dependence: it is stable in acid and
rapidly hydrolyses in alkali (Denny, B.J., et al. Biochemistry 1994, 33, 9045–9051). The incipient drug
MTIC has the opposite properties—relatively stable in alkali but unstable in acid. In this study,
the mechanism of prodrug activation was probed in greater detail to determine whether the reactions
are specific or general acid or base catalysed. Three prodrugs and drugs were investigated, TMZ,
MTIC and the novel dimeric imidazotetrazine EA27. Hydrolysis in a range of citrate-phosphate buffers
(pH 8.0, 7.4, 4.0) was measured by UV spectrophotometry.
Reaction of TMZ and MTIC obeyed single-phase, pseudo-first order kinetics (Figure 1). EA27 was
more complex, showing biphasic but approximately pseudo-first order kinetics, Figure. General acid
or base catalysis indicates that protonation or deprotonation is the rate-limiting step (rls). In biological
milieu, the nature and concentration of other acidic or basic solutes may affect the prodrug activation
reaction. In contrast, specific acid or base catalysis indicates that protonation or deprotonation occurs
before the rls, so catalysis depends only on the local concentration of hydroxide or hydronium ion
(i.e., pH) so the reaction kinetics are not expected to change appreciably in a biological medium.
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Citation
Moody CL, Ahmad L, Ashour A and Wheelhouse RT (2017) Probing Imidazotetrazine Prodrug Activation Mechanisms. In: 25th Conference of GP2A, Meeting report. Pharmaceutics 10(4): 97. Poster presentation, 5.15, (P22).
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Poster presentation