Design an anticancer copper(II) pro-drug based on the flexible IIA subdomain of human serum albumin

Owing to the flexible IIA sub-domain of human serum albumin (HSA), we proposed to rationally design a metal agent with a leaving group, and then regulate a leaving group of metal agent to be displaced by His-242 for improving its delivery efficiency and selectivity. To confirm our hypothesis, we synthesized a copper(II) compound derived from 2-amino-5-chlorophenol 2-hydroxybenzaldehyde Schiff-base, containing a leaving group [pyridine, PRD], namely Cu(L)(PRD). The HSA complex structure revealed that Cu(L)(PRD) binds to the hydrophobic cavity in HSA IIA sub-domain, His242 of HSA replaces the pyridine ligand in Cu compound, coordinating with Cu²⁺. HSA complex enhances cytotoxicity by about 1.4-fold in cancer cells but has no effect on normal cells in vitro through selectively accumulating into cancer cells. Interestingly, HSA complex has stronger anticancer capacity relative to unbound Cu(L)(PRD).