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

doi:10.1016/j.ejmech.2019.01.068

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. Epub 2019 Jan 30.

Authors

Moataz S Hendy¹, Aya A Ali², Lubna Ahmed³, Reham Hossam³, Alaa Mostafa³, Mohamed M Elmazar², Bassem H Naguib⁴, Yasmeen M Attia⁵, Mahmoud Salama Ahmed⁶

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: [email protected].
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: [email protected].

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.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Biomimetic Materials / chemical synthesis*
Biomimetic Materials / chemistry
Biomimetic Materials / metabolism
Biomimetic Materials / pharmacology*
Cell Line, Tumor
Chemistry Techniques, Synthetic
Drug Design*
Estrogen Receptor alpha / antagonists & inhibitors*
Estrogen Receptor alpha / chemistry
Estrogen Receptor alpha / metabolism
Humans
Indoles / chemistry*
Inhibitory Concentration 50
Molecular Docking Simulation
Protein Conformation

Substances

Antineoplastic Agents
Estrogen Receptor alpha
Indoles