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

David S. P. Cardoso, Annamária Kincses, Márta Nové, Gabriella Spengler, Silva Mulhovo, João Aires-de-Sousa, Daniel J. V. A. dos Santos, Maria José U. Ferreira

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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

Original languageEnglish
Article number112985
JournalEuropean Journal of Medicinal Chemistry
Volume210
DOIs
Publication statusPublished - 15 Jan 2021

Keywords

  • 3D-QSAR
  • Alkylation
  • Monoterpene indole alkaloids
  • Multidrug resistance
  • P-glycoprotein
  • Tabernaemontana elegans

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