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

Bioorg Med Chem. 2024 Mar 1:101:117645. doi: 10.1016/j.bmc.2024.117645.

Seyed-Omar Zaraei ¹, Wolfgang Dohle ², Hanan S Anbar ³, Randa El-Gamal ⁴, Bertrand Leblond ⁵, Paul A Foster ⁶, Taleb H Al-Tel ⁷, Barry V L Potter ⁸, Mohammed I El-Gamal ⁹

Affiliations

1 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
2 Medicinal Chemistry and Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
3 Department of Pharmaceutical Sciences, Dubai Pharmacy College for Girls, Dubai 19099, United Arab Emirates.
4 Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
5 Medicinal Chemistry, Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
6 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.
7 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.
8 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: [email protected].
9 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: [email protected].

PMID: 38401456 DOI: 10.1016/j.bmc.2024.117645

Abstract

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 IC₅₀ 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 (GI₅₀ = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI₅₀ 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.

Keywords

Enzyme inhibition; Estrogen receptor; Raloxifene; Steroid sulfatase; Sulfamate.

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