2. Academic Validation
  3. Structure-based design and synthesis of conformationally constrained derivatives of methyl-piperidinopyrazole (MPP) with estrogen receptor (ER) antagonist activity

Structure-based design and synthesis of conformationally constrained derivatives of methyl-piperidinopyrazole (MPP) with estrogen receptor (ER) antagonist activity

  • Bioorg Chem. 2022 Feb;119:105554. doi: 10.1016/j.bioorg.2021.105554.
Mahmoud A Ragab 1,  Mohamed Elagawany 1,  Hoda Daabees 1,  Al-Shaimaa F Ahmed 2,  Eman M Awad 2,  Cyrielle Billon 3,  Bahaa Elgendy 4,  Khaled A M Abouzid 5,  Shaymaa E Kassab 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Buhaira 22516, Egypt.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 3 Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO 63110, USA; Center for Clinical Pharmacology, Washington University School of Medicine, St. Louis College of Pharmacy, St. Louis, MO 63110, USA.
  • 4 Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO 63110, USA; Center for Clinical Pharmacology, Washington University School of Medicine, St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt. Electronic address: [email protected].
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Buhaira 22516, Egypt. Electronic address: [email protected].
PMID: 34923243 DOI: 10.1016/j.bioorg.2021.105554
Abstract

Nuclear Estrogen receptors (ER) are cytoplasmic proteins; translocated to the nucleus to induce transcriptional signals after getting bound to the estrogen hormone. ER activation implicated in Cancer cell proliferation of female reproductive organs. Thus, the discovery of ER antagonists is a reliable strategy to combat estrogen-dependent breast Cancer. Endometrial carcinoma is one of the complications encountered upon long-term therapy by selective Estrogen Receptor modulators (SERMs) like Tamoxifen (TMX) and methyl piperidinopyrazole (MPP). Thus, the ER-full antagonist is a solution to improve the safety of this class of therapeutics during the treatment of breast Cancer. We selected MPP as a lead structure to design conformationally constrained analogs. Structural rigidification is a proven strategy to transform the SERMs into full antagonists. Accordingly, we synthesized 7-methoxy-3-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[g]indazoles (4), (6a-c),(8-12) along with the biphenolic counterparts(13-19)that are the anticipated active metabolites. The 4-nitrophenyl derivative(4)is with the most balanced profile regardingthe in vivoanti-uterotrophic potential (EC50 = 4.160 μM); and the cytotoxicity assay of the corresponding active metabolite(13)against ER+ breast Cancer cell lines (MCF-7 IC50 = 7.200 μM, T-47D IC50 = 11.710 μM). The inconsiderable uterotrophic activities of the elaborated ER-antagonists and weak antiproliferative activity of the compound(13)against ovarian Cancer (SKOV-3 IC50 = 29.800 μM) highlighted it as a good start point to elaborate potential ER-full antagonists devoid of endometrial carcinoma. Extending the pendant chain that protrudes from the 2-(4-(substituted)-phenyl) ring of the new benzo-indazoles is recommended for enhancing the potency based on the binding mode of compound(13)in the ligand-binding domain (LBD) of ER.

Keywords

Antiestrogens; Benzo-indazoles; Breast cancer; ER-full antagonist; Ligand binding domain; Tamoxifen.

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