Deuterated batracylin: deuterium-hydrogen exchange during synthesis and mass spectral analysis
Seltzman, H., Fix, S., & Risbood, P. (2011). Deuterated batracylin: deuterium-hydrogen exchange during synthesis and mass spectral analysis. Journal of Labelled Compounds and Radiopharmaceuticals, 54(4), 206-210.
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 (d(3)-batracylin 5), tetradeuterated in the isoindolo ring (d(4)-batracylin 11), and heptadeuterated in both rings (d(7)-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