Exploring Jolkinol D Derivatives to Overcome Multidrug Resistance in Cancer

• Autor(a) principal: Reis M.A.
• Data de Publicação: 2017
• Outros Autores: Ahmed O.B., Spengler G., Molnár J., Lage H., Ferreira M.-J.U.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://hdl.handle.net/10216/120512
• topic: 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

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.