Inhibition of Human Topoisomerase II by N,N,N-Trimethylethanammonium Iodide Alkylcarbazole Derivatives

Carmela Saturnino, Anna Caruso, Domenico Iacopetta, Camillo Rosano, Jessica Ceramella, Noemi Muià, Annaluisa Mariconda, Maria Grazia Bonomo, Marco Ponassi, Giuseppe Rosace, Maria Stefania Sinicropi, Pasquale Longo

Research output: Contribution to journalArticlepeer-review

Abstract

Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic stage of the disease. Treatment regimens are generally tailored for each patient′s particular situation. However, chemotherapeutic agents are the leading cause of serious drug-related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series of N-alkylcarbazoles derived from ellipticine, an alkaloid with a carbazole skeleton initially used in the treatment of metastatic breast cancer and later dismissed because of poor aqueous solubility and severe side effects. After evaluating the binding modes of our class of newly synthesized compounds with human topoisomerase II (hTopo II), we performed hTopo II decatenation assays, identifying compound 4 f (2-(4-((3-chloro-9H-carbazol-9-yl)pentyl)piperazin-1-yl)-N,N,N-trimethylethanammonium iodide) as a good inhibitor. Moreover, 4 f and 4 g (2-(4-((3-chloro-9H-carbazol-9-yl)hexyl)piperazin-1-yl)-N,N,N-trimethylethanammonium iodide) showed a good anti-proliferative activity toward breast cancer cells, causing apoptosis by activation of the caspase pathway. Interestingly, the activity of these two compounds on triple-negative MDA-MB-231 cells, which tend to be highly metastatic and aggressive, is strictly connected to the observed inhibition of hTopo II.

Original languageEnglish
JournalChemMedChem
DOIs
Publication statusAccepted/In press - Jan 1 2018

Keywords

  • apoptosis
  • caspases
  • docking simulations
  • N-alkylcarbazoles
  • topoisomerase II

ASJC Scopus subject areas

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

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