Bioorthogonal gold-catalyzed carbonyl release and its adaptation for prodrug therapy using multivalent lectin-directed artificial metalloenzymes

Le résumé fourni par la source

In the framework of developing artificial metalloenzyme (ArM) prodrug therapies, two main factors need to be considered; the cancer targeting capabilities of the ArM biocatalyst and the bioorthogonal prodrug activation mechanism. In this study, both these aspects were investigated to develop an example of an anticancer ArM prodrug strategy. To address targeting, the concept of multivalent lectin-directed artificial metalloenzymes was established using a Halotag-PduU-ACG lectin fusion protein (HtPA) functionalized with a gold catalyst. Acting through multivalent binding of hexameric lectin complexes (caused by PduU oligomerization), selective binding to sialic acid-rich cancer cells was proven. To address prodrug activation, the propargylbenzoxime (PBO) group was developed to undergo gold-catalyzed hydroamination, followed by spontaneous N–O bond cleavage to release carbonyl functional groups under mild and physiological conditions. Further adaptation of the PBO group was also explored so that carbonyl release could elicit the synthesis of indole-containing molecules. HtPA-based artificial metalloenzymes were then subsequently applied in cell assays for the activation of a PBO-based prodrug to highlight this alternative approach of an ArM prodrug therapy.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.