{"doi":"10.1021/acs.joc.0c01988","title":"Function-Oriented Synthesis: Design, Synthesis, and Evaluation of Highly Simplified Bryostatin Analogues","abstract":"Using a function-oriented synthesis strategy, we designed, synthesized, and evaluated the simplest bryostatin 1 analogues reported to date, in which bryostatin’s A- and B-rings are replaced by a glutarate linker. These analogues, one without and one with a C26-methyl group, exhibit remarkably different protein kinase C (PKC) isoform affinities. The former exhibited bryostatin-like binding to several PKC isoforms with Ki’s < 5 nM, while the latter exhibited PKC affinities that were up to ∼180-fold less potent. The analogue with bryostatin-like PKC affinities also exhibited bryostatin-like PKC translocation kinetics in vitro, indicating rapid cell permeation and engagement of its PKC target. This study exemplifies the power of function-oriented synthesis in reducing structural complexity by activity-informed design, thus enhancing synthetic accessibility, while still maintaining function (biological activity), collectively providing new leads for addressing the growing list of therapeutic indications exhibited by PKC modulators.","journal":"The Journal of Organic Chemistry","year":2020,"id":83777,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345104,"name":"Jack L. Sloane","orcid":"0000-0002-2564-1002","position":1,"is_corresponding":false},{"id":350854,"name":"Quang H. Luu-Nguyen","orcid":"0000-0003-3698-5270","position":2,"is_corresponding":false},{"id":431427,"name":"Yasuyuki Ogawa","orcid":null,"position":3,"is_corresponding":false},{"id":350853,"name":"Akira Shimizu","orcid":"0000-0002-9475-9661","position":4,"is_corresponding":false},{"id":430604,"name":"Steven M. Ryckbosch","orcid":"0000-0003-3126-0262","position":5,"is_corresponding":false},{"id":430605,"name":"Jefferson H. Tyler","orcid":"0000-0002-4040-4689","position":6,"is_corresponding":false},{"id":350851,"name":"Clayton Hardman","orcid":"0000-0001-5275-7046","position":7,"is_corresponding":false},{"id":345109,"name":"Paul A. Wender","orcid":"0000-0001-6319-2829","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T21:54:32.422022Z","pmid":"33200928","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":[]}