Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans,
was submitted to chemical transformation of the ketone function, yielding 19 azines
(3-21) and 11 semicarbazones (22-32) bearing aliphatic or aromatic substituents. Their
structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments.
Compounds 3-32 were evaluated as multidrug resistance (MDR) reversers through functional
and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model,
overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity
was observed for most derivatives, mainly those containing azine moieties with aromatic
substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were
among the most active, exhibiting strong inhibition at 0.2 mu M. Moreover, most of
the derivatives showed selective antiproliferative effects toward resistant cells,
having a collateral sensitivity effect. In drug combination assays, all compounds
showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18,
20, and 29) were evaluated in the ATPase activity assay, in which all compounds but
12 behaved as inhibitors. To gather further insights on drug-receptor interactions,
in silico studies were also addressed. A QSAR model allowed us to deduce that compounds
bearing bulky and lipophilic substituents were stronger P-gp inhibitors.
