Epoxylathyrol Derivatives

Modulation of ABCB1-Mediated Multidrug Resistance in Human Colon Adenocarcinoma and Mouse T-Lymphoma Cells

Ana M. Matos, Mariana Reis, Noélia Duarte, G. Spengler, J. Molnár, Maria José U Ferreira

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Epoxyboetirane A (1), a macrocyclic diterpene that was found to be inactive as an ABCB1 modulator, was submitted to several chemical transformations, aimed at generating a series of compounds with improved multidrug resistance (MDR)-modifying activity. Overall, 23 new derivatives were prepared, in addition to the already reported epoxylathyrol (2) and methoxyboetirol (3). Their anti-MDR potential was assessed through both functional and chemosensitivity assays on resistant human colon adenocarcinoma and human ABCB1-gene transfected L5178Y mouse lymphoma cells. Structure-activity relationship analysis showed that different substitution patterns led to distinct ABCB1 inhibitory activities, although intrinsic cellular characteristics seemed to influence the modulatory behavior. A considerable enhancement in MDR-modifying activity was observed for aromatic compounds in both cell lines, particularly in 3,17-disubstituted esters derived from 3, a Payne-rearranged Michael adduct of 2. All compounds tested were revealed to interact synergistically with doxorubicin, and ATPase inhibition by three representative MDR-modifying compounds was also investigated. On account of its outstanding ABCB1 inhibitory activity at 0.2 μM and overall remarkable bioactive profile, methoxyboetirane B (22) was found to be a new promising lead for MDR-reversing anticancer drug development.

Original languageEnglish
Pages (from-to)2215-2228
Number of pages14
JournalJournal of Natural Products
Volume78
Issue number9
DOIs
Publication statusPublished - Sep 25 2015

Fingerprint

T-Cell Lymphoma
Aromatic compounds
Diterpenes
Multiple Drug Resistance
Doxorubicin
Modulators
Adenosine Triphosphatases
Assays
Colon
Esters
Adenocarcinoma
Substitution reactions
Genes
Cells
Modulation
Derivatives
Pharmaceutical Preparations
Structure-Activity Relationship
Lymphoma
epoxyboetirane A

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Pharmaceutical Science
  • Analytical Chemistry
  • Organic Chemistry
  • Molecular Medicine
  • Complementary and alternative medicine

Cite this

Epoxylathyrol Derivatives : Modulation of ABCB1-Mediated Multidrug Resistance in Human Colon Adenocarcinoma and Mouse T-Lymphoma Cells. / Matos, Ana M.; Reis, Mariana; Duarte, Noélia; Spengler, G.; Molnár, J.; Ferreira, Maria José U.

In: Journal of Natural Products, Vol. 78, No. 9, 25.09.2015, p. 2215-2228.

Research output: Contribution to journalArticle

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