Discovery of a novel series of tetrahydro-β-carbolines inducing autophagic cell death in human metastatic melanoma

Nermin S. Ahmed, Mohamed Elgendy, Stefan Laufer, Ashraf H. Abadi

Research output: Contribution to journalArticle

Abstract

Herein, we report the synthesis of novel tetrahydro-β-carbolines that induce cell death via the autophagic pathway. Five of the new compounds induced cell death in a panel of patient-derived human metastatic melanoma cells. The autophagic pathway was confirmed using LC3 autophagosome markers; the involvement of ATG7 and Beclin 1 autophagy regulating genes was confirmed using infection with short hairpin RNA (shRNA) to silence Beclin 1 and ATG7. Compound VIII (IC50 = 2.34-5.15 μM) displayed activities greater than cisplatin against a panel of patient-derived human metastatic melanoma cell lines. The structure-activity relationship (SAR) of this class and the role of the absolute stereochemistry and geometrical isomerism are evaluated. Three series of tetrahydro-β-carbolines were designed and synthesized and their abilities to inhibit the growth of different human metastatic melanoma cell lines were investigated. The mechanism of cell death proved to be an autophagic pathway rather than an apoptotic one. The impact of stereochemical aspects on the activity was studied.

Original languageEnglish
Pages (from-to)398-406
Number of pages9
JournalArchiv der Pharmazie
Volume347
Issue number6
DOIs
Publication statusPublished - 2014

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Keywords

  • Anticancer
  • Autophagy
  • Melanoma
  • Non-planar
  • Tetrahydro-β-carbolines

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

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