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Molecules 2017, 22(7), 1183; doi:10.3390/molecules22071183

15N-, 13C- and 1H-NMR Spectroscopy Characterization and Growth Inhibitory Potency of a Combi-Molecule Synthesized by Acetylation of an Unstable Monoalkyltriazene

1
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Glen Hospital, 1001 Decarie Blvd., Montreal H4A 3J1, QC, Canada
2
Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montreal H3A 0B8, QC, Canada
*
Author to whom correspondence should be addressed.
Received: 12 May 2017 / Revised: 24 June 2017 / Accepted: 26 June 2017 / Published: 19 July 2017
(This article belongs to the Section Medicinal Chemistry)
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Abstract

6-(3-Methyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione referred to as EG22 (8a), is an open-chain 3-alkyl-1,2,3-triazene termed “combi-molecule” designed to inhibit poly(adenosine diphosphate ribose) polymerase (PARP) and damage DNA. To delay its hydrolysis, acetylation of N3 was required. Being a monoalkyl-1,2,3-triazene, EG22 could assume two tautomers in solution or lose nitrogen during the reaction, thereby leading to several acetylated compounds. Instead, one compound was observed and to unequivocally assign its structure, we introduced isotopically labeled reagents in its preparation, with the purpose of incorporating 15N at N2 and 13C in the 3-methyl group. The results showed that the 1,2,3-triazene moiety remained intact, as confirmed by 15N-NMR, coupling patterns between the 15N-labeled N2 and the 13C-labeled methyl group. Furthermore, we undertook heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments that permitted the detection and assignment of all four nitrogens in 6-(3-acetyl-3-methyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, referred to as ZSM02 (9a), whose structure was further confirmed by X-ray crystallography. The structure showed a remarkable coplanarity between the N-acetyltriazene and the naphtalimide moiety. Thus, we unequivocally assigned 9a as the product of the reaction and compared its growth inhibitory activity with that of its precursor, EG22. ZSM02 exhibited identical growth inhibitory profile as EG22, suggesting that it may be a prodrug of EG22. View Full-Text
Keywords: 15N-NMR; 1,2,3-triazene; temozolomide; monoalkyltriazene; 4-amino-1,8-naphthalimide 15N-NMR; 1,2,3-triazene; temozolomide; monoalkyltriazene; 4-amino-1,8-naphthalimide
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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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MDPI and ACS Style

Senhaji Mouhri, Z.; Goodfellow, E.; Kelley, S.P.; Stein, R.S.; Rogers, R.D.; J. Jean-Claude, B. 15N-, 13C- and 1H-NMR Spectroscopy Characterization and Growth Inhibitory Potency of a Combi-Molecule Synthesized by Acetylation of an Unstable Monoalkyltriazene. Molecules 2017, 22, 1183.

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