Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes

Vieira, Catarina; Duarte, Noélia; Reis, Mariana; Spengler, Gabriella; Madureira, AM; Molnár, Joséph; Ferreira, Maria José U.

doi:10.1016/j.bmc.2014.09.041

Cited by 34 publications

(51 citation statements)

References 22 publications

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“…This crude residue was suspended in MeOH/H 2 O (1:1) and extracted with EtOAc. The EtOAc soluble fraction was subjected to silica gel flash chromatography to afford 10 crude fractions . Due to the high complexity of these fractions, preliminary 1 H‐NMR analysis was performed in order to prioritise those that were of the most interest .…”

Section: Resultsmentioning

confidence: 99%

“…Euphorbia boetica Boiss. (Euphorbiaceae) aerial parts were extracted with MeOH as previously reported . Briefly, the air‐dried aerial parts were exhaustively extracted with MeOH at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, these species have afforded a large number of structurally unique macrocyclic diterpenes with the lathyrane and jatrophane skeletons . Apart from their importance as biogenetic and chemotaxonomic markers, since they are exclusively isolated from Euphorbiaceae plants, several studies have revealed that they are promising modulators of multidrug resistance (MDR) in tumour cells …”

Section: Introductionmentioning

confidence: 99%

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Effective MDR reversers through phytochemical study of Euphorbia boetica

Neto

Duarte

Pedro

et al. 2019

Phytochemical Analysis

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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 1H‐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 1H‐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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effective MDR reversers through phytochemical study of Euphorbia boetica

Neto

Duarte

Pedro

et al. 2019

Phytochemical Analysis

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“…The HMBCs from H–C(17) ( δ (H) 4.44 and 4.12) to the carbonyl carbon ( δ (C) 170.7) revealed that an acetoxy group was attached to C(17). The position of the remaining acetoxy group was assigned as C(15) by the lack of any HMBC between H–C(3) and the carbonyl carbon as well as the relatively upfield chemical shift of H–C(3) ( δ (H) 4.00) compared to 3‐AcO derivative ( δ (H) 5.44) of lathyrane‐type diterpene, epoxyboetirane A ( 3 ) ( Figure ) . In the NOESY spectrum, the absence of a NOE correlation of H–C(4) and 15‐AcO supported the trans ‐fused ring junction between cyclopentane and the macrocyclic ring skeleton.…”

Section: Resultsmentioning

confidence: 99%

Lathyrane‐Type Diterpenoids from the Seeds of Euphorbia lathyris L. with Inhibitory Effects on NO Production in RAW 264.7 Cells

Lee

Jin

Jang

et al. 2018

Chemistry & Biodiversity

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Bioactivity-guided fractionation of the methanolic extract from the seeds of Euphorbia lathyris led to the isolation of 18 lathyrane-type diterpenoids including a new one, Euphorbia factor L (1). Their chemical structures were elucidated by extensive NMR spectroscopic data including 2D-NMR and HR-ESI-MS as well as CD data. All isolates (1 - 18) were found to inhibit the nitric oxide production in LPS-induced RAW 264.7 macrophages, with their IC values in the range of 11.2 - 52.2 μm.

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“…Previous studies revealed that lathyrane diterpenes extracted from the seeds of E. lathyris L. , Euphorbia factor L1–L11 (EFL1–11), have been considered as promising P-glycoprotein (P-gp) modulators in MDR-mediated resistance8, 9. We have reported the isolation, identification and anticancer activity of EFL1 10 .…”

Section: Introductionmentioning

confidence: 99%

Euphorbia factor L2 induces apoptosis in A549 cells through the mitochondrial pathway

Lin

Tang

Zhang

et al. 2017

Acta Pharmaceutica Sinica B

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Euphorbia factor L2, a lathyrane diterpenoid isolated from caper euphorbia seed (the seeds of Euphorbia lathyris L.), has been traditionally applied to treat cancer. This article focuses on the cytotoxic activity of Euphorbia factor L2 against lung carcinoma A549 cells and the mechanism by which apoptosis is induced. We analyzed the cytotoxicity and related mechanism of Euphorbia factor L2 with an MTT assay, an annexin V-FITC/PI test, a colorimetric assay, and immunoblotting. Euphorbia factor L2 showed potent cytotoxicity to A549 cells. Euphorbia factor L2 led to an increase in reactive oxygen species (ROS) generation, a loss of mitochondrial electrochemical potential, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase, suggesting that Euphorbia factor L2 induced apoptosis through a mitochondrial pathway. The cytotoxic activity of Euphorbia factor L2 in A549 cells and the related mechanisms of apoptotic induction provide support for the further investigation of caper euphorbia seeds.

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Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes

Cited by 34 publications

References 22 publications

Effective MDR reversers through phytochemical study of Euphorbia boetica

Effective MDR reversers through phytochemical study of Euphorbia boetica

Lathyrane‐Type Diterpenoids from the Seeds of Euphorbia lathyris L. with Inhibitory Effects on NO Production in RAW 264.7 Cells

Euphorbia factor L2 induces apoptosis in A549 cells through the mitochondrial pathway

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