Structure-based drug design, synthesis, In vitro, and In vivo biological evaluation of indole-based biomimetic analogs targeting estrogen receptor-α inhibition

Moataz S. Hendy, Aya A. Ali, Lubna Ahmed, Reham Hossam, Alaa Mostafa, Mohamed M. Elmazar, Bassem H. Naguib, Yasmeen M. Attia, Mahmoud Salama Ahmed

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Offering novel scaffolds targeting estrogen receptor creates huge necessity to overcome the evolving resistance developed by tumors. Structure-based drug design coupled with ring opening strategy of the steroids skeleton revealed the potential of indole-based analogs to be synthesized targeting the ligand binding domain of estrogen receptor-α. In vitro studies revealed the potential of the total sub-classes of the synthesized analogs to show anti-proliferative activity against estrogen receptor-dependent cancer cell lines at IC50 ranging from 28.23 to 57.13 μM. This was further validated by evaluating the potential of the synthesized analogs to compete along with estradiol via ER-α ELISA assay to show inhibitory profile at IC50 ranging from 1.76 to 204.75 nM. Two analogs (YMA-005 and YMA-006) showed significant reduction in tumor size at two dose levels with extensive degeneration and necrosis. Both YMA-005 and YMA-006 showed in-situ reduction of ER-α Immunohistochemical expression at both dose levels. Ultimately, novel analogs of indole-based biomimetic of estrone scaffolds were offered as estrogen receptor-α inhibitors.

Original languageEnglish (US)
Pages (from-to)281-290
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume166
DOIs
StatePublished - Mar 15 2019

Keywords

  • Biologically inspired organic synthesis
  • Breast cancer
  • Estrogen receptor-α
  • Indole

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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