Design and synthesis of new antitumor agents with the 1,7-epoxycyclononane framework. Study of their anticancer action mechanism by a model compound

Ángel M. Montaña, Julia Lorenzo, Stefano Ponzano, Maria Filomena Sanasi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

© 2018 Elsevier Ltd This article describes the design, synthesis and biological evaluation of a new family of antitumor agents having the 1,7-epoxycyclononane framework. We have developed a versatile synthetic methodology that allows the preparation of a chemical library with structural diversity and in good yield. The synthetic methodology has been scaled up to the multigram level and can be developed in an enantioselective fashion. The study in vitro of a model compound, in front of the cancer cell lines HL-60 and MCF-7, showed a growth inhibitory effect better than that of cisplatin. The observation of cancer cells by fluorescence microscopy showed the presence of apoptotic bodies and a degradation of microtubules. The study of cell cycle and mechanism of death of cancer cells by flow cytometry indicates that the cell cycle arrested at the G0/G1 phase and that the cells died by apoptosis preferably over necrosis. A high percentage of apoptotic cells at the subG0/G1 level was observed. This indicates that our model compound does not behave as an antimitotic agent like nocodazole, used as a reference, which arrests the cell cycle at G2/M phase. The interaction of anticancer agents with DNA molecules was evaluated by atomic force microscopy, circular dichroism and electrophoresis on agarose gel. The results indicate that the model compound has not DNA as a target molecule. The in silico study of the model compound showed a potential good oral bioavailability.
Original languageEnglish
Pages (from-to)3379-3398
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number12
DOIs
Publication statusPublished - 23 Jul 2018

Keywords

  • AFM
  • Aldol cyclization
  • Anticancer agents
  • Apoptosis
  • Apoptotic nuclei
  • Beta-fragmentation
  • Circular dichroism
  • Cytotoxicity
  • Electrophoresis
  • Flow cytometry
  • Fluorescence microscopy
  • HL-60
  • Hypoiodite reaction
  • Lipinski and Veber's rules
  • MCF-7
  • Microtubules
  • Nicholas reaction
  • Physalins
  • Synthesis of 1,7-epoxycyclononanes
  • [4+3]Cycloaddition

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