Synthesis and evaluation of coumate analogues as estrogen receptor inhibitors for breast cancer therapy

Selvaraj, Jubie; Basheer, A; Yadav, Neetu; Wadhwani, Ashish; Azam, Mohammed Afzal

doi:10.26452/ijrps.v10i3.1455

Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

Venugopal,

Nizampatnam,

Jagadeesh

2023

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Background Selective estrogen receptor modulators (SERMs) block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. If a SERM is in the estrogen receptor, estrogen can't attach to the cancer cell and the cell doesn't receive estrogen's signals to grow and multiply. The goal of this research is to develop small drug-like molecules of novel Benzoazepinone derivatives that mimic the ability of the SERM (Tamoxifene and Raloxifene) to binds with estrogen receptor protein. Methods 2-Phenylethyl bromide undergoes amino alkylation through mannich reaction with CH3NH2 and chloro acetyl chloride, gives 2-chloro-N-methyl-N-phenethylacetamide, which is further undergoing cyclization gives 3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.2-phenylethyl bromide. 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.di-p-toluoyl-1-tartaric acid and 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one. HCl was obtained by treatment with di-p-toluoyl-l-tartaric acid and con. HCl respectively. Finally, this intermediate undergoes nucleophilic addition reactions with different substituted aldehydes. All the compounds were screened for their in-vitro cytotoxicity activity using Vero and MDA MB 231 cell lines by MTT assay. Results IC50 values from Cytotoxicity studies by MTT assay ranges from 11µg/ml to 153µg/ml. A total of 15 compounds were synthesized by using a diverse scheme and the title compounds have exhibited low to high in-vitro anticancer activity with MDA MB 231 cells. Compared to the standard (Raloxifene 6 µg/ml), the developed compounds T2 (35µg/ml), T10 (36µg/ml), T14 (11µg/ml) and T15 (22 µg/ml). Conclusion Finally, four compounds might be used as a lead molecule for future development into a therapeutically viable anti-ER positive breast cancer drug from the benzoazepinone derivatives family.

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Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

Venugopal,

Srinivasa,

Jagadeesh

2024

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Background Selective estrogen receptor modulators (SERMs) block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. If a SERM is in the estrogen receptor, estrogen can't attach to the cancer cell and the cell doesn't receive estrogen's signals to grow and multiply. The goal of this research is to develop small drug-like molecules of novel Benzoazepinone derivatives that mimic the ability of the SERM (Tamoxifene and Raloxifene) to binds with estrogen receptor protein. Methods 2-Phenylethyl bromide undergoes amino alkylation through mannich reaction with CH3NH2 and chloro acetyl chloride, gives 2-chloro-N-methyl-N-phenethylacetamide, which is further undergoing cyclization gives 3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.2-phenylethyl bromide. 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.di-p-toluoyl-1-tartaric acid and 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one. HCl was obtained by treatment with di-p-toluoyl-l-tartaric acid and con. HCl respectively. Finally, this intermediate undergoes nucleophilic addition reactions with different substituted aldehydes. All the compounds were screened for their in-vitro cytotoxicity activity using Vero and MDA MB 231 cell lines by MTT assay. Results IC50 values from Cytotoxicity studies by MTT assay ranges from 11µg/ml to 153µg/ml. A total of 15 compounds were synthesized by using a diverse scheme and the title compounds have exhibited low to high in-vitro anticancer activity with MDA MB 231 cells. Compared to the standard (Raloxifene 6 µg/ml), the developed compounds T2 (35µg/ml), T10 (36µg/ml), T14 (11µg/ml) and T15 (22 µg/ml). Conclusion Finally, four compounds might be used as a lead molecule for future development into a therapeutically viable anti-ER positive breast cancer drug from the benzoazepinone derivatives family.

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Potential Coumarin Thiosemicarbazone Hybrids as Brca-1 Mimetics for Er Positive Breast Cancer Therapy: An in-Silico Approach

Selvaraj¹

2021

JMPAS

4

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The goal of this study is to find a novel class of BRCA-1 mimics for Estrogen Receptor α (ERα) breast cancer that works differently from conventional anti-estrogens. Breast Cancer Susceptibility Protein-1 (BRCA-1) is a protein was discovered to bind to ERα and decrease its function by a direct contact between regions inside BRCA1's amino terminus and the carboxy terminus of ERα. A novel class of hybrids with coumate and thiosemicarbazone scaffolds was created with the premise of developing small compounds that imitate the function of BRCA-1 to down regulate the ERα and inhibit the tumor activity of breast cancer cells. Using Schrodinger 2020-2, ADMET and in silico molecular docking tests of the proposed hybrids were performed on the BRCA-1 binding cavity of ERα. TSCO-XIV and TSCO-III are developed hybrids that have high docking scores and good binding interactions with important residues.

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Synthesis and evaluation of coumate analogues as estrogen receptor inhibitors for breast cancer therapy

Cited by 3 publications

References 15 publications

Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

Potential Coumarin Thiosemicarbazone Hybrids as Brca-1 Mimetics for Er Positive Breast Cancer Therapy: An in-Silico Approach

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