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Mol Pharm. 2018 Jun 4;15(6):2180-2193. doi: 10.1021/acs.molpharmaceut.8b00045. Epub 2018 May 10.

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

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State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources , Guangxi Normal University , Guilin , Guangxi 541003 , China.
School of Pharmacy , Nantong University , Nantong , Jiangsu 226000 , China.
Ben May Department for Cancer Research , University of Chicago , Chicago , Illinois 60637 , United States.


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.


albumin; drug carrier; metal complex; pro-drug; target therapy

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