The 5-aromatic hydantoin-3-acetate derivatives as inhibitors of the tumour multidrug resistance efflux pump P-glycoprotein (ABCB1): Synthesis, crystallographic and biological studies

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• 作者：Ewa Żesławska^a ; ^{zeslawsk@up.krakow.pl" class="auth_mail" title="E-mail the corresponding author} ; Annamá ; ria Kincses^b ; Gabriella Spengler^b ; Wojciech Nitek^c ; Karolina Wyrzuc^d ; Katarzyna Kieć-Kononowicz^d ; Jadwiga Handzlik^d ; ^{j.handzlik@uj.edu.pl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Derivatives of hydantoin ; Multidrug resistance inhibitors ; Crystal structure ; P-glycoprotein (ABCB1)
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：24
• 期：12
• 页码：2815-2822
• 全文大小：1162 K

文摘

A series of arylpiperazine derivatives of hydantoin-3-acetate, including previously obtained 5,5-diphenylhydantoin (1–7) and new-synthesized spirofluorene-hydantoin derivatives (8–12), were investigated in the search for new inhibitors of the tumour multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells. Synthesis of new compounds (8–12) was performed. Crystal structures of two compounds (8 and 11) were determined by X-ray diffraction method. The conformations of the investigated molecules (8 and 11) in the crystalline samples are different. The bent conformation seems to be more favourable for biological activity than the extended one. The efflux pump inhibitory properties of the compounds 1–12 were evaluated in the fluorescence uptake assay using rhodamine 123 dye in mouse T-lymphoma model in vitro. Their cytotoxic action was examined, too. All compounds with methyl acetate moiety displayed high potency to inhibit the MDR efflux pump. The most active compound, methyl 2-(1-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-5,5-diphenylhydantoin-3-yl)acetate (5), tested at 1/10 of verapamil concentration displayed the 9-fold higher P-gp inhibitory action.