Synthesis and SAR Study of Anticancer Protoflavone Derivatives

Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters

Balázs Dankó, Szilárd Tóth, Ana Martins, Máté Vágvölgyi, Norbert Kúsz, J. Molnár, Fang Rong Chang, Yang Chang Wu, G. Szakács, Attila Hunyadi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

There is a constant need for new therapies against multidrug-resistant (MDR) cancer. Natural compounds are a promising source of novel anticancer agents. We recently showed that protoflavones display activity in MDR cancer cell lines that overexpress the P-glycoprotein (P-gp) drug efflux pump. In this study, 52 protoflavones, including 22 new derivatives, were synthesized and tested against a panel of drug-sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics. With the exception of protoapigenone, identified as a weak ABCG2 substrate, all protoflavones bypass resistance conferred by these two transporters. The majority of the compounds were found to exhibit mild to strong (up to 13-fold) selectivity against the MCF-7Dox and KB-V1 cell lines, but not to transfected MDR cells engineered to overexpress the MDR transporters. Our results suggest that protoflavones can overcome MDR cancer by evading P-gp-mediated efflux.

Original languageEnglish
Pages (from-to)850-859
Number of pages10
JournalChemMedChem
Volume12
Issue number11
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

P-Glycoprotein
Cytotoxicity
Cells
Derivatives
Pharmaceutical Preparations
Antineoplastic Agents
KB Cells
Cell Line
Neoplasms
Genes
Pumps
Transfection
Substrates
Therapeutics
protoapigenone

Keywords

  • collateral sensitivity
  • cross-resistance
  • MDR cancer
  • P-glycoprotein
  • protoflavones

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Synthesis and SAR Study of Anticancer Protoflavone Derivatives : Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters. / Dankó, Balázs; Tóth, Szilárd; Martins, Ana; Vágvölgyi, Máté; Kúsz, Norbert; Molnár, J.; Chang, Fang Rong; Wu, Yang Chang; Szakács, G.; Hunyadi, Attila.

In: ChemMedChem, Vol. 12, No. 11, 01.01.2017, p. 850-859.

Research output: Contribution to journalArticle

Dankó, Balázs ; Tóth, Szilárd ; Martins, Ana ; Vágvölgyi, Máté ; Kúsz, Norbert ; Molnár, J. ; Chang, Fang Rong ; Wu, Yang Chang ; Szakács, G. ; Hunyadi, Attila. / Synthesis and SAR Study of Anticancer Protoflavone Derivatives : Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters. In: ChemMedChem. 2017 ; Vol. 12, No. 11. pp. 850-859.
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