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

Ewa Zesławska, Annamária Kincses, G. Spengler, Wojciech Nitek, Karolina Wyrzuc, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalBioorganic and Medicinal Chemistry
DOIs
Publication statusAccepted/In press - Feb 5 2016

Fingerprint

Hydantoins
Phenytoin
Multiple Drug Resistance
P-Glycoprotein
Tumors
Acetates
Pumps
Derivatives
Rhodamine 123
Conformations
T-Cell Lymphoma
Verapamil
X-Ray Diffraction
Lymphoma
Neoplasms
Coloring Agents
Fluorescence
Bioactivity
Assays
Crystal structure

Keywords

  • Crystal structure
  • Derivatives of hydantoin
  • Multidrug resistance inhibitors
  • P-glycoprotein (ABCB1)

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

The 5-aromatic hydantoin-3-acetate derivatives as inhibitors of the tumour multidrug resistance efflux pump P-glycoprotein (ABCB1) : Synthesis, crystallographic and biological studies. / Zesławska, Ewa; Kincses, Annamária; Spengler, G.; Nitek, Wojciech; Wyrzuc, Karolina; Kieć-Kononowicz, Katarzyna; Handzlik, Jadwiga.

In: Bioorganic and Medicinal Chemistry, 05.02.2016.

Research output: Contribution to journalArticle

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