Synthesis, biological evaluation, and stability studies of raloxifene mono- and bis-sulfamates as dual-targeting agents.

Autor: Zaraei SO; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates., Dohle W; Medicinal Chemistry and Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom., Anbar HS; Department of Pharmaceutical Sciences, Dubai Pharmacy College for Girls, Dubai 19099, United Arab Emirates., El-Gamal R; Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt., Leblond B; Medicinal Chemistry, Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom., Foster PA; Institute of Metabolism and Systems Research, 2(nd) Floor IBR Tower, University of Birmingham, Birmingham B15 2TT, United Kingdom; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom., Al-Tel TH; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates., Potter BVL; Medicinal Chemistry and Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom; Medicinal Chemistry, Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Electronic address: barry.potter@pharm.ox.ac.uk., El-Gamal MI; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: drmelgamal2002@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Mar 01; Vol. 101, pp. 117645. Date of Electronic Publication: 2024 Feb 16.
DOI: 10.1016/j.bmc.2024.117645
Abstrakt: All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC 50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7-9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI 50  = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI 50 of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7-9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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