Deuterated batracylin: deuterium-hydrogen exchange during synthesis and mass spectral analysis

• Published in: Journal of labelled compounds & radiopharmaceuticals 2011-04, Vol.54 (4), p.206-210
• Main Authors: Seltzman, Herbert H., Fix, Scott E., Risbood, Prabhakar
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; batracylin; Biological and medical sciences; deuterium; General aspects; mass spectrum; Medical sciences; ortho exchange; Pharmacology. Drug treatments
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.1847

Deuterium‐labeled analogs of the topoisomerase inhibitor batracylin were prepared for metabolism studies to further its evaluation as an antitumor agent. Established syntheses of unlabeled batracylin were adapted for the preparation of deuterated batracylin that was trideuterated in the quinazoline ring (d3‐batracylin 5), tetradeuterated in the isoindolo ring (d4‐batracylin 11), and heptadeuterated in both rings (d7‐batracylin 12). Extensive exchange of deuterium or hydrogen in the quinazoline ring was observed from an intermediate in the final concentrated sulfuric acid promoted deblocking/cyclodehydration step of the synthesis. Introduction of deuterated concentrated sulfuric acid in the final step both retained the label in the quinazoline‐labeled product and enabled extended labeling of a more exhaustively deuterated analog. Batracylin itself did not readily exchange aromatic protons under the reaction conditions but did loose and scramble deuterium atoms during mass spectral analysis leading to an under calculation of the deuterium content in the quinazoline ring. These results identify a chemical exchange process that can either undo, maintain, or facilitate the labeling process and also mass spectral analyses issues that must be taken into account to characterize and utilize these analogs and, more broadly, that can be recognized as potentially applicable to other classes of compounds. Copyright © 2010 John Wiley & Sons, Ltd. Batracylin's precursor exchanges deuterium/hydrogen from the diaminophenyl ring prior to, but minimally after, the cyclodehydration that affords batracylin, impacting deuterium incorporation. Mass spectral analysis also suffers exchange resulting in under calculation of incorporation. The use of deuterated sulfuric acid in the cyclodehydration maintains deuterium in the quinazoline ring. Copyright © 2010 John Wiley & Sons, Ltd.