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

Cátia Vieira, Noélia Duarte, Mariana A. Reis, G. Spengler, Ana Margarida Madureira, J. Molnár, Maria José U Ferreira

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Aiming to optimize macrocyclic lathyrane-type diterpenes as effective Pgp modulators, the phytochemical study of the methanolic extract of Euphorbia boetica aerial parts was carried out. Two new macrocyclic 6,17-epoxylathyrane-type diterpenes, named epoxyboetiranes A (1) and B (2), along with three known analogues (3-5) were isolated. Epoxyboetirane A (1), a triacetate isolated in large amounts, was hydrolyzed to give epoxylathyrol (6). In order to study the effect of the substitution pattern of the macrocyclic scaffold on MDR reversal, 6 was acylated with aroyl, phenylacetyl, cinnamoyl and alkanoyl chlorides/anhydrides, yielding eight new esters, epoxyboetiranes C-J (7-14). The ability of compounds 1-14 as P-glycoprotein (Pgp, ABCB1) modulators was evaluated through combination of transport and chemosensitivity assays, using L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. In the transport assay, excepting 1, 3 and 6, the compounds, at non-cytotoxic concentrations, displayed strong MDR reversing activity in a dose-dependent mode, exhibiting all the new acyl derivatives (7-14) a many fold increase in the activity when compared with 1. Apart from 11 and 12, all compounds exhibited remarkable synergistic effects in combination with doxorubicin. An ATPase assay, using membrane vesicles from mammalian cells overexpressing Pgp, was also performed with two representatives of the modulators (4 and 5). The results suggest that both compounds compete with substrates for the Pgp drug-binding sites.

Original languageEnglish
Pages (from-to)6392-6400
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number22
DOIs
Publication statusPublished - Nov 15 2014

Fingerprint

Diterpenes
Modulators
Assays
Euphorbia
Anhydrides
Phytochemicals
P-Glycoprotein
Cells
Doxorubicin
Adenosine Triphosphatases
Lymphoma
Binding Sites
Scaffolds
Cell Line
Membranes
Esters
Substitution reactions
Genes
Pharmaceutical Preparations
Antennas

Keywords

  • ATPase activity
  • Euphorbia boetica
  • Macrocyclic diterpenes
  • Multidrug resistance
  • P-glycoprotein

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes. / Vieira, Cátia; Duarte, Noélia; Reis, Mariana A.; Spengler, G.; Madureira, Ana Margarida; Molnár, J.; Ferreira, Maria José U.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 22, 15.11.2014, p. 6392-6400.

Research output: Contribution to journalArticle

Vieira, Cátia ; Duarte, Noélia ; Reis, Mariana A. ; Spengler, G. ; Madureira, Ana Margarida ; Molnár, J. ; Ferreira, Maria José U. / Improving the MDR reversal activity of 6,17-epoxylathyrane diterpenes. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 22. pp. 6392-6400.
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