title: Terminal functionalized thiourea-containing dipeptides as multidrug-resistance reversers that target 20S proteasome and cell proliferation.
abstract: A series of inhibitors of 20S proteasome based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for inhibition of 20S proteasome and the effects of multidrug-resistance reversers. These compounds exhibited significant selectivity to the β5-subunit of the human 20S proteasome with IC50values at submicromolar concentrations. A docking study of the most active compound 6i revealed key interactions between 6i and the active site of the 20S proteasome in which the thiourea moiety and a nitro group were important for improving activity. In particular, compound 6i appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by inhibition of the activity of 20S proteasome and induce apoptosis. In addition, 6i-induced apoptosis was significantly facilitated in NCI-H460/DOX cells that had been pretreated with inhibitors of P-gp. Mechanistically, compound 6i might trigger apoptotic signalling pathway. Thus, we conclude that dipeptide derivatives containing the thiourea moiety may be the potential inhibitors of proteasome with the ability to reverse multidrug resistance.
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Qin
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Ri-Zhen
authors.initials: RZ
authors.lastname: Huang
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Gui-Yang
authors.initials: GY
authors.lastname: Yao
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Liao
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China. Electronic address: panym2013@hotmail.com.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Pan
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China. Electronic address: whengshan@163.com.
authors.forename: Heng-Shan
authors.initials: HS
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; D013890:Thiourea
keywords: Anti-tumor; Multidrug resistance; Proteasome; Pseudopeptides; Thioureas