Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 13, Pages 8564-8579Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00248
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This study proposed a multitargeted palladium agent based on the specific residue(s) of human serum albumin for treating cancer. The Pd agent showed significant capacity in inhibiting tumor growth through multiple actions on different components of the tumor microenvironment.
To obtain next-generation metal drugs that can overcomethe deficienciesof platinum (Pt) drugs and treat cancer more effectively, we proposedto develop a multitargeted palladium (Pd) agent to the tumor microenvironment(TME) based on the specific residue(s) of human serum albumin (HSA).To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazonecompounds to obtain a Pd agent (5b) with significant cytotoxicity.The HSA-5b complex structure revealed that 5b bound to the hydrophobiccavity in the HSA IIA subdomain and then His-242 replaced a leavinggroup (Cl) of 5b, coordinating with the Pd center. The invivo results showed that the 5b/HSA-5b complex had significantcapacity of inhibiting tumor growth, and HSA optimized the therapeuticbehavior of 5b. In addition, we confirmed that the 5b/HSA-5b complexinhibited tumor growth through multiple actions on different componentsof TME: killing cancer cells, inhibiting tumor angiogenesis, and activatingT cells.
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