Synthesis of novel heterobifunctional isocyanato cross-linkers and their applications for the preparation of 10-hydroxycamptothecin and SN-38 conjugates with melanotransferrin p97

Novel heterobifunctional cross-linkers with an isocyanato group, a protected carboxylic group, and a linear chain spacer are synthesized in high yield by coupling monofunctionalized PEG with 1,6-diisocyanatohexane. The isocyanato groups of those linkers are highly reactive and are efficient reagents to couple with the hydroxy groups of 10-hydroxycamptothecin and SN-38 under mild conditions to give a useful precursor for the synthesis of their bioconjugates with proteins such as melanotransferrin p97.