Strategy for Imidazotetrazine Prodrugs with Anticancer Activity Independent of MGMT and MMR

The imidazotetrazine ring is an acid-stable precursor and prodrug of highly reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and h...

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Published inACS medicinal chemistry letters Vol. 3; no. 12; pp. 965 - 968
Main Authors Garelnabi, Elrashied A. E, Pletsas, Dimitrios, Li, Li, Kiakos, Konstantinos, Karodia, Nazira, Hartley, John A, Phillips, Roger M, Wheelhouse, Richard T
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.12.2012
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Imidazotetrazine
aziridinium
cancer
Temozolomide
13C NMR
DNA
ANTITUMOR DRUG TEMOZOLOMIDE
DECOMPOSITION
C-13 NMR
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Summary:The imidazotetrazine ring is an acid-stable precursor and prodrug of highly reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and have antitumor activity independent of the O6-methylguanine-DNA methyltransferase and DNA mismatch repair constraints that limit the use of Temozolomide.
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ISSN:1948-5875
1948-5875
DOI:10.1021/ml300132t