The Synthesis and Anticancer Activity of the Trastuzumab–Doxorubicin Antibody–Drug Conjugate Using Strain-Promoted Alkyne–Azide Coupling

Antibody–drug conjugates (ADCs) are target-specific drugs for the treatment of cancer. Fifteen antibody–drug conjugates have been approved so far for clinical use, while others remain in preclinical stages. We demonstrate here an example of the conjugation of a monoclonal antibody (trastuzumab) with a drug (doxorubicin) employing strain-promoted alkyne–azide coupling (SPAAC) reaction. This is an example of a “green” reaction because it is atom-efficient, and no side products are formed. The reaction is driven forward by release of strain in the triple bond of the seven-membered ring permitting regiospecific formation of triazole rings. Both trastuzumab and doxorubicin are currently in clinical use, but with safety issues involving each of them. The new ADC has the potential to increase the proapoptotic markers such as Bax, cleaved caspase 9, and Cytc at 5 and 10 μg/mL against the human breast tumor cell line BT474.