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Development of Sulfamoylated 4‑(1-Phenyl‑1H‑1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer
Abstract
We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells. The most active compound, 5l, demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC50 value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity.
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Authors (15)
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Witold Kozak
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Janusz Rak Prof.
- Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdansk, Poland
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Konrad Kubiński
- Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1i, 20-708 Lublin, Poland
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Maciej Masłyk
- Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1i, 20-708 Lublin, Poland
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Aleksandra Martyna
- Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1i, 20-708 Lublin, Poland
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Joanna Wietrzyk
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Rudolfa Weigla 12, 53-114 Wrocław, Poland
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Marta Świtalska
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Rudolfa Weigla 12, 53-114 Wrocław, Poland
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Alessio Nocentini dr
- Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy
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Claudiu T. Supuran
- Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy
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Full text
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- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1021/acs.jmedchem.1c02220
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Details
- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
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JOURNAL OF MEDICINAL CHEMISTRY
no. 65,
pages 5044 - 5056,
ISSN: 0022-2623 - Language:
- English
- Publication year:
- 2022
- Bibliographic description:
- Biernacki K., Ciupak O., Daśko M., Rachon J., Kozak W., Rak J., Kubiński K., Masłyk M., Martyna A., Śliwka-Kaszyńska M., Wietrzyk J., Świtalska M., Nocentini A., Supuran C. T., Demkowicz S.: Development of Sulfamoylated 4‑(1-Phenyl‑1H‑1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer// JOURNAL OF MEDICINAL CHEMISTRY -Vol. 65,iss. 6 (2022), s.5044-5056
- DOI:
- Digital Object Identifier (open in new tab) 10.1021/acs.jmedchem.1c02220
- Sources of funding:
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- Project Steroid sulfatase inhibitors based on sulfamated derivatives of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenol as potential anticancer agents
- Centre for Knowledge and Technology Transfer (Gdansk University of Technology) and the Ministry of Science and Higher Education (Poland) through the “Incubator of Innovation+” program-grant agreement no. CTWT/40/II+.
- Verified by:
- Gdańsk University of Technology
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