{"doi":"10.1126/science.aea9310","title":"Three-component assembly and structure-function relationships of (–)-gukulenin A","abstract":"α-Tropolones comprise an unsaturated seven-membered ring bearing a hydroxyl substituent adjacent to a polarized carbon-oxygen π bond. This polarization imparts a permanent molecular dipole and aromatic stabilization to the ring, resulting in distinct physical properties, including affinity for divalent metals and ambiphilic reactivity. Among secondary metabolites that contain α-tropolones, the pseudodimeric isolate (–)-gukulenin A ( 7 ) stands out for its complexity and has shown promise in treating mouse models of ovarian cancer. In this study, we describe an enantioselective synthesis of (–)-gukulenin A ( 7 ). Key steps include a directed C–H arylation, a tandem Grob fragmentation–alkylation, an innovative synthesis of methyl tropolone ethers, a multicomponent cross-coupling, and a thermal carbonyl-ene reaction. Structure-function studies establish the dimeric tropolone and aldehyde substructures as drivers of cytotoxicity.","journal":"Science","year":2025,"id":527505,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":1404828,"name":"Zechun Wang","orcid":null,"position":1,"is_corresponding":false},{"id":1404248,"name":"Joshua B. Combs","orcid":"0009-0000-8834-5836","position":2,"is_corresponding":false},{"id":1404249,"name":"Timothy B. Wright","orcid":"0000-0003-4986-4654","position":3,"is_corresponding":false},{"id":1404250,"name":"Lei Chen","orcid":"0000-0003-4952-5150","position":4,"is_corresponding":false},{"id":1404251,"name":"Boxu Lin","orcid":"0009-0008-7550-2407","position":5,"is_corresponding":false},{"id":1166141,"name":"Ryan Holmes","orcid":"0009-0003-5928-4837","position":6,"is_corresponding":false},{"id":1404252,"name":"Bo Qin","orcid":"0000-0003-0622-4008","position":7,"is_corresponding":false},{"id":393375,"name":"Joonseok Oh","orcid":"0000-0002-7616-1949","position":8,"is_corresponding":false},{"id":304470,"name":"Jason M. Crawford","orcid":"0000-0002-7583-1242","position":9,"is_corresponding":false},{"id":304471,"name":"Seth B. Herzon","orcid":"0000-0001-5940-9853","position":10,"is_corresponding":false},{"id":1404247,"name":"Vaani Gupta","orcid":"0009-0003-8879-0528","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41231967","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":[]}