Development of benzofuran-derived sulfamates as dual aromatase-steroid sulfatase inhibitors (DASIs): design, synthesis and biological evaluation.

Eissa, Ahmed G., Gozzi, Francesca, Aloqab, Oqab Mohammed M, Parrish, Charlotte E., Mohamed, Nadira, Shiali, Irene, Al-Baldawi, Harith, Foster, Paul A. and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2025. Development of benzofuran-derived sulfamates as dual aromatase-steroid sulfatase inhibitors (DASIs): design, synthesis and biological evaluation. RSC Medicinal Chemistry 16 (4) , pp. 1606-1618. 10.1039/d4md00795f

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Abstract

Resistance of oestrogen receptor-positive (ER+) breast cancer, the most prevalent type of breast cancer accounting for ∼70% of all cases, to current therapies necessitates the study of alternative strategies. One promising strategy is the multi-targeting approach using dual aromatase-steroid sulfatase inhibitors (DASIs). Herein, we describe the development of DASIs using a common benzofuran pharmacophore. Triazole benzofuran sulfamates were found to have low nM aromatase (Arom) inhibitory activity but no steroid sulfatase (STS) inhibitory activity (IC50 > 10 μM); by contrast, benzofuran ketone sulfamates demonstrated low nM STS inhibitory activity but no Arom inhibitory activity (IC50 > 1 μM). The addition of a methyl group at the 3rd position of the benzofuran ring in the benzofuran ketone sulfamate 19 (R1 = CH3) had a notable effect, resulting in dual aromatase and STS inhibitory activities with the 4-chloro derivative 19b (Arom IC50 = 137 nM, STS IC50 = 48 nM) and 4-methoxy derivative 19e (Arom IC50 = 35 nM, STS IC50 = 164 nM) optimal for dual inhibition. Arom/STS inhibition results combined with molecular dynamics studies provided a clear rationale for the activity observed.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Professional Services > Advanced Research Computing @ Cardiff (ARCCA) Schools > Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: Title: cc by, Type: cc by
Publisher:	Royal Society of Chemistry
ISSN:	2632-8682
Date of First Compliant Deposit:	14 February 2025
Date of Acceptance:	7 January 2025
Last Modified:	20 Jun 2025 13:51
URI:	https://orca.cardiff.ac.uk/id/eprint/176182

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