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

Seyed-Omar Zaraei, Wolfgang Dohle, Hanan S. Anbar, Randa El-Gama, Bertrand Leblond, Paul A. Foster, Taleb H. Al-Tel, Barry V. L. Potter, Mohammed I. El-Gamal

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

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.
Original languageEnglish
Article number117645
JournalBioorganic & Medicinal Chemistry
Volume101
Early online date16 Feb 2024
DOIs
Publication statusPublished - 1 Mar 2024

Data Availability Statement

Data will be made available on request.

Funding

The authors are grateful to University of Sharjah , United Arab Emirates, for financial support (grant Nos. 2101110153 , 2201110169 , 2301110174 , and Drug Design and Discovery research group operational fund). This work was also supported in part by Sterix Ltd., a member of the Ipsen Group. We also thank the National Cancer Institute Developmental Therapeutics Program (NCI DTP) for providing in vitro screening resources. The authors are grateful to University of Sharjah, United Arab Emirates, for financial support (grant Nos. 2101110153, 2201110169, 2301110174, and Drug Design and Discovery research group operational fund). This work was also supported in part by Sterix Ltd. a member of the Ipsen Group. We also thank the National Cancer Institute Developmental Therapeutics Program (NCI DTP) for providing in vitro screening resources.

FundersFunder number
Ipsen Group
National Cancer Institute Developmental Therapeutics Program
Sterix Ltd
National Cancer Institute
University of Sharjah2201110169, 2301110174, 2101110153

    Keywords

    • Enzyme inhibition
    • Estrogen receptor
    • Raloxifene
    • Steroid sulfatase
    • Sulfamate

    ASJC Scopus subject areas

    • Drug Discovery
    • Molecular Medicine
    • Molecular Biology
    • Biochemistry
    • Clinical Biochemistry
    • Pharmaceutical Science
    • Organic Chemistry

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