Mercaptoalkanol-derived self-immolative linkers for bioconjugates. Synthesis and analysis

Abstract

Many of the anticancer compounds discovered through synthesis or bioprospecting activities are found to be equally toxic to healthy cells and tumors. Consequently, these compounds are not considered as promising drug candidates worthy of further study. This project seeks to develop a novel chemical toolkit that can be utilized to increase the therapeutic value of such toxic compounds by decreasing the number of potential anticancer compounds that are sidelined. Several prodrug strategies exist whereby compounds can be chemically modified in such a manner that their selective transport and delivery to cancer cells becomes possible. However, a key requirement is that these modifications are temporary in their nature. One such strategy is to reversibly link cytotoxic compounds to a tumor homing delivery vector via a selfeliminating linker. The focus of this project was on the design and synthesis of a set, or toolkit, of heterobifunctional self-eliminating linkers that can be utilized in prodrug synthesis. A series of self-immolative linkers containing a thiol-reactive group at one end and a hydroxyl- or amine-reactive group at the other have been prepared from mercaptoalkonols. The utility of these reagents for preparations of bioconjugates has been explored by reacting the linkers with appropriately functionalized model drugs and peptides. Degradation studies of a series of conjugates with different linkers reveal that the structure of the linkers has a significant impact on their stability.