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Mechanisms of Action of Silane-Substituted Anti-Cancer Imidazotetrazines
Summers, H.S. Bradshaw, T.D. Stevens, M.F.G. Wheelhouse, Richard T.
Summers, H.S.
Bradshaw, T.D.
Stevens, M.F.G.
Wheelhouse, Richard T.
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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
Silane-substituted imidazotetrazines 1,2 were investigated for their activity as anticancer prodrugs
related to temozolomide (TMZ). The TMS-derivative 1 showed an activity profile against TMZ
susceptible and resistant cell lines very similar to TMZ; in contrast, the SEM-derivative 2 showed
activity irrespective of MGMT expression or MMR deficiency (Table).
Probing the prodrug activation mechanism by NMR kinetic studies determined that the TMS
compound 1 follows a reaction pathway and time-course very similar to temozolomide. 1H-NMR
spectra of the reaction mixture showed considerable incorporation of deuterium into the final
alkylation products of the reaction (methanol and methyl phosphate) as had previously been shown
for temozolomide (Wheelhouse, R.T., et al. Chem. Commun. 1993, 15, 1177–1178). The SEM-derivative
2 reacted more rapidly than TMZ or TMS-derivative 1. Somewhat surprisingly, the silane remained
intact throughout the experiment and the observed reaction was the hydrolysis of the imidazo-tetrazine
to ultimately release formaldehyde hydrate and 2-TMS-ethanol.
In conclusion, TMS-derivative 1 is a diazomethane precursor with prodrug activation mechanism,
kinetics and anti-cancer activity in vitro similar to TMZ. In contrast, the SEM derivative 2 was more
rapidly hydrolysed, a precursor of 2-TMS-ethanol and had activity in vitro different from TMZ.
2-TMS-ethanol was previously reported as a non-toxic compound in mice (Voronkov, M.G., et al.
Dokl. Akad. Nauk SSSR 1976, 229, 1011–1013) and is known as a substrate for alcohol dehydrogenase
(Zong, M.-H., et al. Appl. Microbiol. Biotechnol. 1991, 36, 40–43) and as a modest inhibitor of
acetylcholinesterase (Aberman, A., et al. Biochim. Biophys. Acta 1984, 791, 278–280; Cohen, S.G., et al.
J. Med. Chem. 1985, 28, 1309–1313).
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Summers HS, Bradshaw TD, Stevens MFG and Wheelhouse RT (2017) Mechanisms of Action of Silane-Substituted Anti-Cancer Imidazotetrazines. In: 25th Conference of GP2A, Meeting report. Pharmaceutics 10(4): 97. Poster presentation, 5.16, (P23).
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Poster presentation