Yi Gou

Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain

To synergistically enhance the selectivity and efficiency of anticancer copper drugs, we proposed and built a model to develop anticancer copper pro-drugs based on the nature of human serum albumin (HSA) IIA subdomain and cancer cells. Three copper(II) compounds of a 2-hydroxy-1-naphthaldehyde benzoyl hydrazone Schiff-base ligand in the presence pyridine, imidazole, or indazole ligands were synthesized (C1-C3). The structures of three HSA complexes revealed that the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. Among them, the pyridine and imidazole ligands of C1 and C2 are replaced by Lys199, and His242 directly coordinates with Cu(II). The indazole and Br ligands of C3 are replaced by Lys199 and His242, respectively. Compared with the Cu(II) compounds alone, the HSA complexes enhance cytotoxicity in MCF-7 cells approximately 3-5-fold, but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent. We find that the HSA complex has a stronger capacity for cell cycle arrest in the G2/M phase of MCF-7 by targeting cyclin-dependent kinase 1 (CDK1) and down-regulating the expression of CDK1 and cyclin B1. Moreover, the HSA complex promotes MCF-7 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.

Developing an Anticancer Copper(II) Pro-Drug Based on the His242 Residue of the Human Serum Albumin Carrier IIA Subdomain

To increase delivery efficiency, anticancer activity, and selectivity of anticancer metal agents in vivo, we proposed to develop the anticancer metal pro-drug based on His242 residue of the human serum albumin (HSA) carrier IIA subdomain. To confirm our hypothesis, we prepared two Cu(II) compounds [Cu(P4 mT)Cl and Cu(Bp44 mT)Cl] by modifying Cu(II) compound ligand structure. Studies with two HSA complex structures revealed that Cu(P4 mT)Cl bound to the HSA subdomain IIA via hydrophobic interactions, but Cu(Bp44 mT)Cl bound to the HSA subdomain IIA via His242 replacement of a Cl atom of Cu(Bp44 mT)Cl, and a coordination to Cu(2+). Furthermore, Cu(II) compounds released from HSA could be regulated at different pHs. In vivo data revealed that the HSA-Cu(Bp44 mT) complex increased coppers selectivity and capacity of inhibiting tumor growth compared to Cu(Bp44 mT)Cl alone.

Developing Anticancer Ferric Prodrugs Based on the N-Donor Residues of Human Serum Albumin Carrier IIA Subdomain.

To improve the selectivity, delivery, and activity of ferric (Fe) anticancer agents, we design prodrugs based on N-donor residues of the human serum albumin (HSA) carrier IIA subdomain. We synthesized six Fe(III) compounds derived from 2-hydroxy-1-naphthaldehyde thiosemicarbazone (7-12). HSA complex structure revealed that Fe compound binds to the hydrophobic cavity in the HSA IIA subdomain. Lys199 and His242 of HSA replace the two Cl atoms of Fe compound, coordinating with Fe(3+). In vivo data revealed that compound 12 and HSA-12 complex inhibit the growth of the liver tumor and that the HSA-12 complex has stronger targeting ability and therapeutic efficacy than compound 12 alone. In addition, our results have shown that compound 12 and HSA-12 complex induce Bel-7402 cell death possible by several mechanisms.

Developing an Anticancer Copper(II) Multitarget Pro-Drug Based on the His146 Residue in the IB Subdomain of Modified Human Serum Albumin

Designing a multitarget anticancer drug with improved delivery and therapeutic efficiency in vivo presents a great challenge. Thus, we proposed to design an anticancer multitarget metal pro-drug derived from thiosemicarbazone based on the His146 residue in the IB subdomain of palmitic acid (PA)-modified human serum albumin (HSA-PA). The structure-activity relationship of six Cu(II) compounds with 6-methyl-2-formylpyridine-4N-substituted thiosemicarbazones were investigated, and then the multitarget capability of 4b was confirmed in cancer cell DNA and proteins. The structure of the HSA-PA-4b complex (HSA-PA-4b) revealed that 4b is bound to the IB subdomain of modified HSA, and that His146 replaces the nitrate ligand in 4b, coordinating with Cu2+, whereas PA is complexed with the IIA subdomain by its carboxyl forming hydrogen bonds with Lys199 and His242. In vivo data showed that 4b and the HSA-PA-4b complex inhibit lung tumor growth, and the targeting ability and therapeutic efficacy of the PA-modified HSA complex was stronger than 4b alone.