Scheme 1.

Synthesis of glucuronide-capped self-immolative doxorubicin prodrugs. Synthetic strategy for glucuronide-capped self-immolative DOX prodrugs containing 1-3 aromatic units (AU, colored in yellow) in the spacer structure (DOX-AU1-3). Precursors D-1-3 were synthesized from the carbamate bond formation (steps i-iii) between the compound A and the corresponding isocyanate derivative of B (obtained after reaction with diphenylphosphoryl azide (DPPA) in TEA). DOX-AU1-3 were synthesized by carbamate bond formation between the corresponding activated benzyl alcohol of D-1-3 (E-1-3) and DOX·HCl in triethylamine (TEA) (steps iv and v). The final deprotection step (vi) was carried out at 37 °C in PBS (pH 7.4).