{"doi":"10.1016/j.ejps.2025.107249","title":"Designing fluorescent estrogen mimetic 7-hydroxycoumarin probe substrates for human sulfotransferase enzymes","abstract":"ABSTRACT Sulfonation is one of drug metabolism reactions affecting homeostasis of estrogens. C-3 aryl substituted 7-hydroxycoumarins are fluorescent estrogen mimetics; i.e., the hydroxyl groups of both estrogens and 7-hydroxycoumarins are conjugated by human sulfotransferases (SULTs). Sulfonation of the 7-hydroxyl group by SULTs decreases the fluorescence of 7-hydroxycoumarins. Sulfonation of a series of 7-hydroxycoumarins by human SULTs was determined based on this property. SULT subtype-specific binding interactions of 7-hydrocoumarins were assessed against the modelled optimal arrangement needed for sulfonation. 3-(4-Methoxyphenyl)-7-hydroxycoumarin ( 11 ) and 3-(4-hydroxyphenyl)-7-hydroxycoumarin ( 9 ) were selective substrates for SULT1E1, whereas 3-(1H-1,2,4-triazol-1-yl)-7-hydroxycoumarin ( 14 ) was a selective SULT1A1 substrate. Other tested 7-hydroxycoumarin were sulfonated by more than two SULTs. Sulfonation of most 7-hydroxycoumarins by SULT1A1 or SULT1C4 followed Michaelis-Menten kinetics, while substrate inhibition kinetics occurred in sulfonation of several derivatives by SULT1E1. Selective sulfonation of derivatives 9 and 11 by SULT1E1 was due to the enzyme’s long and cylindrical active site that assures optimal 7-hydroxyl group placement in the precursory reaction state. SULT1A1 and SULT1C4 preferred smaller derivatives as substrates than the SULT1E. Estrogens potently inhibited the sulfonation of 3,4-dimethyl-7-hydroxycoumarin ( 4 ) by SULT1E1 (IC50 below 1 µM). SULT1A1 and SULT1C4 were less potently inhibited by the estrogens. Several 7-hydroxycoumarin derivatives share common binding interaction patterns with the estrogens at SULT1E1 and SULT1A1 active sites. Fluorescent 7-hydroxycoumarins could serve as convenient probe substrates for SULTs to evaluate their inhibition by new chemical entities during drug development. 7-Hydroxycoumarins 9 or 11 could be used as selective probe substrates for SULT1E1 and 14 for SULT1A1.","journal":"European Journal of Pharmaceutical Sciences","year":2025,"id":573675,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1480838,"name":"Pekka A. Postila","orcid":"0000-0002-2947-7991","position":1,"is_corresponding":false},{"id":1480839,"name":"Pankaj Kumar Singh","orcid":"0000-0002-4774-6358","position":2,"is_corresponding":false},{"id":535410,"name":"Juhani Huuskonen","orcid":"0000-0003-4594-2803","position":3,"is_corresponding":false},{"id":1480840,"name":"Juri M. Timonen","orcid":"0000-0001-7720-2215","position":4,"is_corresponding":false},{"id":402400,"name":"Muluneh M. Fashe","orcid":"0000-0003-3661-8585","position":5,"is_corresponding":false},{"id":1481210,"name":"Rasikh Hussain","orcid":null,"position":6,"is_corresponding":false},{"id":1481211,"name":"Zaeema Aqip","orcid":null,"position":7,"is_corresponding":false},{"id":535411,"name":"Olli Kärkkäinen","orcid":"0000-0003-0825-4956","position":8,"is_corresponding":false},{"id":330145,"name":"Hannu Raunio","orcid":null,"position":9,"is_corresponding":false},{"id":328525,"name":"Olli T. Pentikäinen","orcid":"0000-0001-7188-4016","position":10,"is_corresponding":false},{"id":328526,"name":"Risto O. Juvonen","orcid":"0000-0001-9240-7673","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:57:36.753600Z","pmid":"40885279","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}