2. Academic Validation
  3. Rational design, synthesis, antiproliferative activity against MCF-7, MDA-MB-231 cells, estrogen receptors binding affinity, and computational study of indenopyrimidine-2,5-dione analogs for the treatment of breast cancer

Rational design, synthesis, antiproliferative activity against MCF-7, MDA-MB-231 cells, estrogen receptors binding affinity, and computational study of indenopyrimidine-2,5-dione analogs for the treatment of breast cancer

  • Bioorg Med Chem Lett. 2022 May 15:64:128668. doi: 10.1016/j.bmcl.2022.128668.
Iqra Ejaz 1,  Muhammad Aamir Javed 1,  Muhammad Saeed Jan 2,  Muhammad Ikram 3,  Abdul Sadiq 4,  Sajjad Ahmad 4,  Umer Rashid 5
Affiliations

Affiliations

  • 1 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, Pakistan.
  • 2 Department of Pharmacy, University of Swabi, Swabi 23430, KP, Pakistan.
  • 3 Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, Pakistan.
  • 4 Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000 Dir (L), KP, Pakistan.
  • 5 Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, Pakistan. Electronic address: umerrashid@cuiatd.edu.pk.
PMID: 35276362 DOI: 10.1016/j.bmcl.2022.128668
Abstract

Based on the structural architecture of estrogen receptors (ER) agonists/antagonists, we rationally designed and synthesized indenopyrimidine-2,5-dione analogs as a starting point of current research targeting estrogen receptors. These analogs were evaluated for their antiproliferative activities against breast Cancer MCF-7 (ER+), MDA-MB-231 (ER-) and non-cancerous HEK-293 cells using MTT assay. Compounds with high antiproliferative activity against MCF-7 breast Cancer cells were found devoid of cytotoxicity against HEK-293 cells. Competitive binding assay of estrogen receptors ERα and ERβ showed that diethanolamine derivative of 4-trifluoromethyl phenyl derivative 30 displayed 77.5-fold strong binding affinity towards ERα (IC50 = 0.004 μM) as compared to ERβ (IC50 = 0.31 μM). The calculated RBA value of compound 30 indicated that it has greater affinity with ER than estradiol. By docking studies, we demonstrated that high binding affinity with ERα is due to binding orientation and interaction of CF3 with a number of key amino acid residues present in the active site of ERα.

Keywords

Breast cancer; Estrogen receptor (ER); MCF-7 cancer cells, Antiangiogenesis; Tricyclic indenopyrimidine-2,5-dione.

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