Exploring Jolkinol D Derivatives to Overcome Multidrug Resistance in Cancer

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.

This study was financially supported by Fundação para a Ciencia e a Tecnologia (FCT), Portugal (project PTDC/QEQ-MED/0905/2012; PhD grant SFRH/BD/72915/2010), German Egyptian Research Long-term Scholarship (GERLS) Program 2014 (57076387) provided by the German Academic Exchange Service (DAAD), and the contribution of the Foundation for Cancer Research Szeged, Hungary. We also acknowledge Carlos Cordeiro, Faculdade de Ciencias, Universidade de Lisboa, for HRMS data (FCT, REDE/1501/REM/2005).