Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells

Aiming at generating a series of monoterpene indole alkaloids with enhanced multidrug resistance (MDR) reversing activity in cancer, two major epimeric isolated from Tabernaemontana elegans, tabernaemontanine (1) and dregamine (2), were derivatized by alkylation the nitrogen. Twenty-six new derivatives (3–28) prepared reaction different aliphatic aromatic halides, whose structures elucidated mainly NMR, including 2D NMR experiments. Their MDR reversal ability was evaluated through functional assay, using as models resistant human colon adenocarcinoma ABCB1-gene transfected L5178Y mouse lymphoma cells, overexpressing P-glycoprotein (P-gp), flow cytometry. A considerable increase found for most derivatives, being strongest P-gp inhibitors those sharing N-phenethyl moieties, displaying outstanding inhibitory activity, associated weak cytotoxicity. Chemosensitivity assays also performed model combination chemotherapy same cell lines, studying vitro interactions between compounds antineoplastic drug doxorubicin. Most have shown strong synergistic doxorubicin, highlighting their potential reversers. QSAR explored insights on drug-receptor interaction, it that lipophilicity bulkiness features although linear correlations not observed.