Please use this identifier to cite or link to this item: https://hdl.handle.net/10216/120512
Author(s): Reis M.A.
Ahmed O.B.
Spengler G.
Molnár J.
Lage H.
Ferreira M.-J.U.
Title: Exploring Jolkinol D Derivatives to Overcome Multidrug Resistance in Cancer
Publisher: American Chemical Society
Issue Date: 2017
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. © 2017 The American Chemical Society and American Society of Pharmacognosy.
Subject: antineoplastic agent
doxorubicin
jolkinoate a
jolkinoate b
jolkinoate c
jolkinoate d
jolkinoate n
jolkinoate o
jolkinoate p
jolkinoate q
jolkinoate r
jolkinoate s
jolkinoate t
jolkinoate u
jolkinocarbonate a
jolkinocarbonate b
jolkinol d derivative
multidrug resistance protein 1
unclassified drug
verapamil
ABCB1 protein, human
antineoplastic agent
caspase 3
diterpene
doxorubicin
Jolkinol D
lathyrane
macrocyclic compound
multidrug resistance protein
animal cell
antineoplastic activity
apoptosis
Article
chemosensitivity
chemosensitization
controlled study
drug potentiation
enzyme activity
human
human cell
hydrolysis
malignant neoplasm
mouse
multidrug resistance
nonhuman
pancreas cancer
stereospecificity
stomach cancer
structure activity relation
animal
chemical structure
chemistry
drug effects
drug resistance
Euphorbia
isolation and purification
Lymphoma, T-Cell
metabolism
tumor cell line
Animals
Antineoplastic Agents, Phytogenic
Apoptosis
Caspase 3
Cell Line, Tumor
Diterpenes
Doxorubicin
Drug Resistance, Neoplasm
Euphorbia
Humans
Lymphoma, T-Cell
Macrocyclic Compounds
Mice
Molecular Structure
P-Glycoproteins
Structure-Activity Relationship
URI: https://hdl.handle.net/10216/120512
Source: Journal of Natural Products, vol. 80(5), p. 1411-1420
Document Type: Artigo em Revista Científica Internacional
Rights: openAccess
Appears in Collections:CIIMAR - Artigo em Revista Científica Internacional

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