Design, synthesis and biological profile of new inhibitors of multidrug resistance associated proteins carrying a polycyclic scaffold

Alessandra Bisi, Silvia Gobbi, Lucia Merolle, Giovanna Farruggia, Federica Belluti, Angela Rampa, Joseph Molnar, Emil Malucelli, Concettina Cappadone

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Following the identification of a novel polycyclic scaffold, leading to the previously reported potent P-gp modulator 1, a small series of easily affordable derivatives bearing a properly selected nitrogen-containing but-2-ynyl side chain was now synthesized and tested to evaluate the MDR reverting activity on two different experimental models. All compounds proved not to be cytotoxic when tested alone and more potent chemosensitizers than the reference verapamil. Some of them showed remarkable effects in combination with doxorubicin, being able to induce apoptotic cell death due to their reverting activity. In particular, 2a and 2c could be regarded as non-toxic new potential chemosensitizers, being able to interfere with different ABC proteins. Moreover, the intrinsic cytotoxicity of compound 1 could broaden its employment as MDR modulator. These results also seem to confirm the polycyclic core of these compounds as a potential new pharmacophoric carrier in medicinal chemistry.

Original languageEnglish
Pages (from-to)471-480
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume92
DOIs
Publication statusPublished - Mar 6 2015

Keywords

  • Anticancer
  • Chemosensitizers
  • Drug design
  • MDR modulators
  • MDR-1
  • P-glycoprotein

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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