Nitrogen-containing Andrographolide Derivatives with Multidrug Resistance Reversal Effects in Cancer Cells

Ribeiro, Joana R. L. and Szemerédi, Nikoletta and Gonçalves, Bruno M. F. and Spengler, Gabriella and Afonso, Carlos A. M. and Ferreira, Maria-José U. (2024) Nitrogen-containing Andrographolide Derivatives with Multidrug Resistance Reversal Effects in Cancer Cells. RSC MEDICINAL CHEMISTRY, .. pp. 1-14. ISSN 2632-8682

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Abstract

Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3–25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1–25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 μM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC50 = 5.47 ± 0.22 μM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.

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