Effective MDR reversers through phytochemical study of Euphorbia boetica. Issue 5 (19th June 2019)

• Record Type: Journal Article
• Authors: Neto, Sara; Duarte, Noélia; Pedro, Cecília; Spengler, Gabriella; Molnár, Joséph; Ferreira, Maria‐José U.; Lanzotti, Virginia; Grauso, Laura
• Is Part Of: Phytochemical analysis. Volume 30:Issue 5(2019)
• Page Start: 498
• Page End: 511
• Publication Date: 2019-06-19
• Subjects: Euphorbia -- lathyrane -- macrocyclic diterpenes -- multidrug resistance -- P‐glycoprotein; Plants -- Analysis -- Periodicals; Plants -- chemistry -- Periodicals; 572.2
• DOI: 10.1002/pca.2841
• Languages: English
• ISSNs: 0958-0344

Abstract

Abstract: Introduction: Macrocyclic diterpenes from Euphorbia species were found to be promising modulators of multidrug resistance (MDR), a complex phenomenon that hampers the effectiveness of cancer therapy. Objective: To find new effective MDR reversers through the phytochemical study of E. boetica, including isolation and molecular derivatisation. Material and methods: The phytochemical study of E. boetica was performed through chromatographic techniques. Preliminary analysis of crude chromatographic fractions from the methanol extract was carried out by 1 H‐NMR in order to prioritise the study of those having macrocyclic diterpenes. Polyamide resin was used to remove chlorophylls. Molecular derivatisation of isolated compounds comprised hydrolysis, reduction and acylation reactions. The structural identification of compounds was performed through analysis of spectroscopic data, mainly one‐dimensional‐ and two‐dimensional‐NMR. The MDR reversing activity was assessed using a combination of transport and chemosensitivity assays, in mouse lymphoma (L5178Y‐MDR) and Colo320 cell models. Results: The 1 H‐NMR study of crude fractions and application of a straightforward method to remove chlorophylls, allowed the effortless isolation of two lathyrane‐type diterpenes in large amounts, including the new polyester, euphoboetirane B (1 ). Taking advantage of the chemical functions of 1, 13 new derivatives were prepared. Several compounds showed to be promising modulators of P‐glycoprotein (P‐gp), in resistant cancer cells. Most of the compounds tested revealed to interact synergistically with doxorubicin. Conclusion: These results corroborate the importance of macrocyclic lathyrane diterpenes as effective lead compounds for the reversal of MDR. Abstract : Aiming at finding new effective compounds for reversing multidrug resistance (MDR), by developing P‐gp modulators, the phytochemical study of E. boetica was conducted leading to the isolation of a new lathyrane diterpene in large amounts, allowing the preparation of thirteen derivatives. In a functional assay, most of the compounds were able to modulate the efflux activity of P‐gp on multidrug resistant cancer cells. In drug combination assays, they synergistically interact with doxorubicin, indicating that may be promising anti‐MDR leads.