Synthesis of a lysosome-targeting aminoferrocene-based prodrug NCure2

06 November 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Prodrugs can achieve highly specific targeting of cancer cells. Therefore, their application can improve the therapy of cancer diseases. The best aminoferrocene-based prodrug developed in the group of Mokhir is N-ferrocenyl-N-[4-(1-piperidinylmethyl)benzyl]aminocarboyloxymethyl-phenylboronic acid pinacol ester, NCure2 (Angew. Chem. Int. Ed. 56 (2017), 15545). It targets lysosomes of cancer cells due to the presence of a basic N alkylpiperidine moiety in its structure. In the lysosomes, the prodrug is activated by H2O2 due to the presence of a H2O2 responsive, Lewis acidic boronic acid pinacol ester moiety. Due to the zwitter-ionic nature of NCure2 its synthesis is low yielding, purification is laborious that leads to the product losses. In this work we report on the significantly improved synthetic protocol for preparation of HCl salt of NCure2 by introducing the boronic acid moiety in the last synthetic step via Miyaura borylation conditions that allowed the facile purification of the final product by its precipitation. This new approach makes NCure2·HCl easily synthetically accessible that will facilitate its further pre-clinical and clinical studies.

Keywords

Ferrocene
Cancer
Prodrug
Improved Synthesis
Lysosome

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