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

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

  • Eur J Med Chem. 2019 Mar 15:166:281-290. doi: 10.1016/j.ejmech.2019.01.068.
Moataz S Hendy 1,  Aya A Ali 2,  Lubna Ahmed 3,  Reham Hossam 3,  Alaa Mostafa 3,  Mohamed M Elmazar 2,  Bassem H Naguib 4,  Yasmeen M Attia 5,  Mahmoud Salama Ahmed 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt.
  • 2 Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt; Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt.
  • 3 Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 5 Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt; Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt. Electronic address: Yasmeen.attia@bue.edu.eg.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt; Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Mahmoud.salama@bue.edu.eg.
PMID: 30731397 DOI: 10.1016/j.ejmech.2019.01.068
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.

Keywords

Biologically inspired organic synthesis; Breast cancer; Estrogen receptor-α; Indole.

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