Tritiation of azido‐labeled diiodo cabazitaxel (Jevtana) and docetaxel (Taxotere) derivatives to generate ³H‐photoaffinity probes

Abstract

Radiolabelled azidophenyl analogues can make powerful photoaffinity probes for the identification of molecular targets. We describe our efforts to prepare tritiated azidophenyl analogues of the taxols cabazitaxel and docetaxel. Late-stage tritiation by isotope exchange with diiodo precursors resulted in reduction of the azide moiety, which could only be overcome by addition of high excess of a sacrificial azide. Iodine-deuterium exchange experiments on a model system established that deiodination with concomitant azide reduction is a general problem when performing such isotope-exchange reactions on azide-containing aryl iodides.

Method Development and Syntheses Examples of Isotopically Labeled Compounds to Foster Operational Excellence in Pharma Industry

“…The successful tritium labeling of both compounds was finally achieved by addition of a ‘sacrificial’ azide to prevent overreduction of the taxane azidophenyl moiety. 39 Excess of tritium reacted with the victim azide leaving the taxane azide untouched. By this protocol we obtained the desired material with specific activities of 51 and 55 Ci mmol –1 ( 1.9 and 2.0 TBq mmol –1 ), respectively, which was sufficient for their use in Pgp transporter study experiments.…”