CHEMICAL SCIENCE

Sun Yat-sen University designs high-efficiency and low-toxic metal complex prodrugs through a new strategy


On May 5, 2022, Professor Zhao Chunshun’s research group from the School of Pharmacy of Sun Yat-sen University published an article entitled “A Stimuli-Responsive Small-Molecule Metal-Carrying Prochelator: A Novel Prodrug Design Strategy for Metal” at the Angeo andte Chemie International Edition Complexes” new study.

The research group proposes a design strategy for the proligand carrying metal ions as a novel metal complex prodrug, which can specifically trigger the in situ formation of the active metal complex.

Doctoral students Huang Zeqian, Luo Yong and Zhang Tao of Sun Yat-sen University are the first authors of the paper, and Professor Zhao Chunshun of Sun Yat-sen University is the corresponding author of the paper.

Designing prodrugs that can be selectively activated at the lesion site is an important means to achieve high efficiency and low toxicity of drugs. Professor Zhao Chunshun’s research group of the School of Pharmacy of Sun Yat-sen University proposed a new design strategy for metal complex prodrugs, that is, pre-ligand prodrugs carrying metal ions (see Figure 1A). These prodrugs are single small molecule compounds consisting of three parts: proligands, chemically sensitive bonds in response to pathological features, and groups that can carry metal ions. Its activation principle is: under specific conditions, the chemically sensitive bonds in the compound are selectively broken, releasing a ligand prototype, and the metal ions carried within the competitive chelating molecule form a biologically active metal complex in situ and play a therapeutic role.

In this paper, a prolific prodrug carrying Cu2+ was designed using diethyl dithiocarbamic acid (DTC) as a model. DTC can form complex Cu (DTC)2 with Cu2+, which has significant antitumor activity, while the same dose of DTC or Cu2+ has no significant antitumor activity. Based on the difference in the levels of reactive oxygen species (hydrogen peroxide, etc.) between tumor cells and normal cells, hydrogen peroxide-sensitive prodrugs (DPBD and DPPBD) based on DTC and Cu2+ were designed (see Figures 1 B and 1 C), aiming to achieve in situ synthesis of Cu (DTC) 2 through the characteristics of the tumor microenvironment and exert antitumor effects.

The results showed that DPBD can chelate Cu2+ in a 1:1 coordination ratio to form a metal complex prodrug DPBD-Cu. At high hydrogen peroxide levels, DPBD-Cu can be broken to release free DTC. Since DTC has a stronger Cu2+ chelation capacity than DPA, DTC can competitively chelate Cu2+ within the DPBD-Cu molecule to form a biologically active Cu (DTC)2 in situ. The results of in vitro and in vitro experiments show that DPBD-Cu has a good anti-tumor effect.

Fig. 1: (A) schematic of the design of the procolytic prodrug carrying metal ions; (B) small molecule prodrugs DPBD and DPPBD, and negative control compound DPD; (C) schematic diagram of the mechanism by which the prodrug DPBD-Cu generates Cu (DTC)2

Figure 2: DPBD can carry Cu2+ to form a metal complex prodrug DPBD-Cu

Figure 3: DPBD-Cu can generate Cu (DTC)2 under hydrogen peroxide conditions

The proligand prodrug design strategy proposed in the paper has the advantages of a single small molecule compound and the characteristics of in situ generation of active metal complexes after triggering, which provides a reference for the prodrug design of metal complexes. (Source: Science Network)

Related paper information:https://doi.org/10.1002/anie.202203500



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