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    Mechanisms of Action of Silane-Substituted Anti-Cancer Imidazotetrazines

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    Poster presentation (635.1Kb)
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    Publication date
    2017
    Author
    Summers, H.S.
    Bradshaw, T.D.
    Stevens, M.F.G.
    Wheelhouse, Richard T.
    Keyword
    Imidazotetrazines, silane-substituted; Anti-cancer; Mechanisms; Anticancer prodrugs
    Rights
    © 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).
    URI
    http://hdl.handle.net/10454/15622
    Version
    Published version
    Citation
    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).
    Link to publisher’s version
    https://doi.org/10.3390/ph10040097
    Type
    Poster presentation
    Collections
    Life Sciences Publications

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