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Structure-based design and synthesis of conformationally constrained derivatives of methyl-piperidinopyrazole (MPP) with estrogen receptor (ER) antagonist activity.
- Source :
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Bioorganic chemistry [Bioorg Chem] 2022 Feb; Vol. 119, pp. 105554. Date of Electronic Publication: 2021 Dec 13. - Publication Year :
- 2022
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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 (EC <subscript>50</subscript>  = 4.160 μM); and the cytotoxicity assay of the corresponding active metabolite(13)against ER+ breast cancer cell lines (MCF-7 IC <subscript>50</subscript>  = 7.200 μM, T-47D IC <subscript>50</subscript>  = 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 IC <subscript>50</subscript>  = 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.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Estrogen Receptor Antagonists chemical synthesis
Estrogen Receptor Antagonists chemistry
Female
Humans
Ligands
Molecular Structure
Piperidines chemical synthesis
Piperidines chemistry
Pyrazoles chemical synthesis
Pyrazoles chemistry
Rats
Rats, Wistar
Receptors, Estrogen metabolism
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Drug Design
Estrogen Receptor Antagonists pharmacology
Piperidines pharmacology
Pyrazoles pharmacology
Receptors, Estrogen antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 119
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34923243
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105554