Abstract
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 µM. 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.
Highlights
Dregamine (1) derivatives were reported as promising multidrug resistant (MDR) reversers [13,14,15], prompting us to carry out new chemical modifications to obtain 19 azines (3–21) and 11 semicarbazone (22–32) derivatives
These results showed that compounds 4, 6, 16, and 19 had their best pose at the modulator binding site (M-site) and exhibited a strong binding affinity with the target coupled with strong cross-interactions with both P-gp halves, and were considered as non-competitive inhibitors
As ongoing research on the optimization of monoterpene indole alkaloids as MDRreversers, this work was focused on the generation of new analogs by modifying the ketone group of dregamine (1), yielding 19 azines (3–21) and 11 semicarbazones (22–32)
Summary
One of the main concerns regarding chemotherapy failure in cancer and infectious diseases is multidrug resistance (MDR). This complex phenomenon can be classified as intrinsic or acquired resistance. The former comprises all natural features of an organism or cell that makes them resistant to a certain drug, whereas acquired MDR involves a decrease in the susceptibility to a drug, generally due to a certain genetic modification [1,2]. One well-known mechanism of acquired resistance results from the overexpression of ATP binding cassette (ABC) transporters, which extrude anticancer drugs using ATP, decreasing the intracellular drug concentration below the therapeutic window [3,4]
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