Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin

Abstract

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to 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 thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

“…Thiosemicarbazones remain an intriguing and topical class of anticancer agents that continue to attract considerable attention. ,− The current evaluation of novel PPP4pT analogues included a thorough analysis of structure–activity relationships, revealing a substantial influence of the substituents on electrochemistry and biological efficacy. The correlation between redox potentials and Hammett substituent parameter ( σ p ) demonstrated the significant impact of the substituents through both inductive and resonance effects.…”

Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis

“…On one hand, it has been one of the most promising strategies for designing a novel next-generation anticancer metal agent by rational screening the metal ion and ligand to synthesize metal complexes; − on the other hand, the lipophilicity and anticancer activity of thiosemicarbazone compounds can be improved by modifying the hydrogen atom(s) at their N4 position with another group(s). ,− To obtain a new next-generation anticancer metal drug with high efficiency and low toxicity, we designed and synthesized a series of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds by modifying the N3 position with an alkyl group or a phenyl group and then synthesized and characterized the corresponding Ru­(III) complexes. The crystal structures of Ru­(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes ( 1b–4b ) were determined by X-ray crystallography (Figure ).…”

Human Serum Albumin-Platinum(II) Agent Nanoparticles Inhibit Tumor Growth Through Multimodal Action Against the Tumor Microenvironment

“…The improvement on the SI may be due to differences in their uptake by cancer cells and normal cells (Figure E). In addition, the toxicity of Pt­(Dp44mT)Cl to HL-7702 normal cells was lower than that of the Pd thiosemicarbazone complex synthesized by us previously, and its antitumor activity against 143B cells was higher than that of the Gd thiosemicarbazone complex . Therefore, the optimal compound Pt­(Dp44mT)Cl was selected for subsequent biological studies.…”

“…However, metal compounds inevitably have problems such as a lack of targeting and several side effects . Drug delivery strategies are the most promising avenues to overcome these limitations. , Human serum albumin (HSA), as the most predominant plasma protein, is also one of the most promising drug carriers, and it has the superiorities of nontoxicity, nonantigenicity, biocompatibility, and biodegradability. − In recent years, some studies on the interaction of drugs with HSA have been extensively conducted to evaluate the binding and transport mechanisms of drugs in vivo. − The HSA-metal drug complex delivery system is a novel approach that directly binds metal drugs to HSA, which can not only avoid the destruction of metal drugs by endogenous molecules during the transport of metal drugs in vivo but also promote the selective accumulation of metal drugs in tumor tissues and targeted release in tumor cells. − …”