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J Nat Prod. 2017 May 26;80(5):1411-1420. doi: 10.1021/acs.jnatprod.6b01084. Epub 2017 Apr 19.

Exploring Jolkinol D Derivatives To Overcome Multidrug Resistance in Cancer.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa , Avenue Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
2
Institute of Pathology, University Hospital Charité , 10117 Berlin, Germany.
3
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged , Dóm tér 10, H-6720 Szeged, Hungary.

Abstract

Macrocyclic monoacyl lathyrane derivatives bearing a benzoyl moiety were previously found to be strong ABCB1 modulators. To explore the effects of different substituents of the aromatic moiety, 14 new compounds (1.1-1.7, 1.10, and 2.1-2.4) were prepared from jolkinol D (1), obtained from Euphorbia piscatoria, and from jolkinodiol (2), its hydrolysis derivative. Compounds 1.8 and 1.9, having aliphatic moieties, were also obtained. The reversal of ABCB1-mediated MDR was evaluated through functional and chemosensitivity assays on the human ABCB1-gene-transfected L5178Y mouse T-lymphoma cell line. Structure-activity relationships showed that addition of electron-donating groups to the aromatic moiety improved the activity. The effects on the ATPase activity of the strongest modulator (1.3) and the inactive jolkinol D (1) were also investigated and compared. Moreover, in the chemosensitivity assay, most of the compounds interacted synergistically with doxorubicin. Compounds 1.1-1.10 and 2.1-2.4 were further assessed for their collateral sensitivity effect against the human cancer cells: EPG85-257 (gastric) and EPP85-181 (pancreatic), and the matching drug-selected cells EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, and EPP85-181RNOV. The most promising ones (1.8 and 1.10) along with compound 3, previously selected, were investigated as apoptosis inducers. The compounds were able to induce apoptosis through caspase-3 activation, with significant differences being observed between the parental and resistant cells.

PMID:
28421773
DOI:
10.1021/acs.jnatprod.6b01084
[Indexed for MEDLINE]

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