{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:22:14Z","timestamp":1768954934166,"version":"3.49.0"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFF0502400"],"award-info":[{"award-number":["2021YFF0502400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Marine Service Industry Program of Shandong Province","award":["2025"],"award-info":[{"award-number":["2025"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["42576087"],"award-info":[{"award-number":["42576087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Strategic Priority Research Program of the Chinese Academy of Sciences","award":["XDB1060000"],"award-info":[{"award-number":["XDB1060000"]}]},{"DOI":"10.13039\/100014103","name":"Key Research and Development Program of Shandong Province","doi-asserted-by":"publisher","award":["2024CXPT028"],"award-info":[{"award-number":["2024CXPT028"]}],"id":[{"id":"10.13039\/100014103","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014103","name":"Key Research and Development Program of Shandong Province","doi-asserted-by":"publisher","award":["2025CXPT012"],"award-info":[{"award-number":["2025CXPT012"]}],"id":[{"id":"10.13039\/100014103","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taishan Scholars Program","award":["tsqn2023-12302"],"award-info":[{"award-number":["tsqn2023-12302"]}]},{"name":"Shandong Laboratory Program","award":["SYS202205"],"award-info":[{"award-number":["SYS202205"]}]},{"name":"Youth Fund of the Natural Science Foundation of Shandong Province","award":["ZR2023QD162"],"award-info":[{"award-number":["ZR2023QD162"]}]},{"name":"Fundamental Research Projects of Science & Technology Innovation and Development Plan in Yantai City","award":["2023JCYJ057"],"award-info":[{"award-number":["2023JCYJ057"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>The discovery of structurally novel anti-tumor agents remains a crucial objective in cancer drug research. In this study, we systematically explored the bioactivity potential of sarocladione (5), a structurally unique marine-derived 14-membered ring diketone steroid. Guided by a function-oriented strategy, seven new derivatives (6\u201313) were synthesized based on an efficient biomimetic synthesis of sarocladione. Evaluation of their antiproliferative activities against human cancer cell lines demonstrated that the intact macrocyclic scaffold is indispensable for activity. Extension of the conjugated \u03c0-system led to the identification of compound 8, which exhibited approximately four-fold enhanced potency against HCT116 cells (IC50 = 1.86 \u00b5M) compared with the parent natural product. Stereochemical analysis further revealed the critical role of the (5R)-configuration at C-5. Phenotypic investigations indicated that compound 8 induces concentration-dependent G2\/M phase cell cycle arrest, followed by apoptosis, suggesting a cell cycle-dependent antiproliferative effect. Overall, this study highlights sarocladione as a promising marine-derived scaffold for further antiproliferative optimization.<\/jats:p>","DOI":"10.3390\/md24010048","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T11:27:58Z","timestamp":1768908478000},"page":"48","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Synthesis of Marine Sarocladione Derivatives with Potential Anticancer Activity"],"prefix":"10.3390","volume":"24","author":[{"given":"Xiao-Mei","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling-Xiu","family":"Kong","sequence":"additional","affiliation":[{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guan-Ying","family":"Han","sequence":"additional","affiliation":[{"name":"Shandong Fengjin Biopharmaceuticals Co., Ltd., Yantai 264117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghan","family":"Gui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China"},{"name":"Shanghai Academy of Natural Sciences (SANS), Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-9726","authenticated-orcid":false,"given":"Xu-Wen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","first-page":"195","article-title":"Progress in approved drugs from natural product resources","volume":"22","author":"Luo","year":"2024","journal-title":"Chin. J. Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Shao, F., Shen, Q.-Y., Yang, Z.-F., Yang, W.-Q., Lu, Z.-X., Zheng, J., Zhang, L.-M., and Li, H.-Y. (2024). Research Progress of Natural Active Substances with Immunosuppressive Activity. Molecules, 29.","DOI":"10.3390\/molecules29102359"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural Products in Drug Discovery: Advances and Opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4660","DOI":"10.1002\/ptr.7099","article-title":"Natural products: A lead for drug discovery and development","volume":"35","author":"Chopra","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"nwac206","DOI":"10.1093\/nsr\/nwac206","article-title":"Natural products and drug discovery","volume":"9","author":"Newman","year":"2022","journal-title":"Natl. Sci. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s10295-015-1723-5","article-title":"Natural Product Discovery: Past, Present, and Future","volume":"43","author":"Katz","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"He, S., Ma, M., Epstein, S., and Yin, Y.-C. (2023). Editorial: Microbes from marine distinctive environments. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1300210"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.phytol.2024.01.001","article-title":"Exploring the potential of marine natural products in drug development: A comprehensive review","volume":"59","author":"Banday","year":"2024","journal-title":"Phytochem. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1039\/D5NP00048C","article-title":"Discovery, biosynthesis, and bioactivities of peptidic natural products from marine sponges and sponge-associated bacteria","volume":"42","author":"Zhong","year":"2025","journal-title":"Nat. Prod. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Shi, J.-Y., Yu, M., Chen, W.-K., Chen, S.-J., Qiu, Y.-K., Xu, Z.-Y., Wang, Y., Huang, G.-L., and Zheng, C.-J. (2024). Recent Discovery of Nitrogen Heterocycles from Marine-Derived Aspergillus Species. Mar. Drugs, 22.","DOI":"10.3390\/md22070321"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.apsb.2018.10.003","article-title":"Marine sponges of the genus Stelletta as promising drug sources: Chemical and biological aspects","volume":"9","author":"Wu","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_13","first-page":"74","article-title":"Diversity-oriented synthesis of marine sponge derived hyrtioreticulins and their anti-inflammatory activities","volume":"20","author":"Chen","year":"2022","journal-title":"Chin. J. Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107512","DOI":"10.1016\/j.cclet.2022.05.026","article-title":"Yonarolide A, an unprecedented furanobutenolide-containing norcembranoid derivative formed by photoinduced intramolecular [2+2] cycloaddition","volume":"34","author":"Du","year":"2023","journal-title":"Chin. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e202401179","DOI":"10.1002\/cbdv.202401179","article-title":"Design and Synthesis of Marine Polybrominated Diphenyl Ether Derivatives as Potential Anti-Inflammatory Agents","volume":"21","author":"Gao","year":"2024","journal-title":"Chem. Biodiversity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5925","DOI":"10.1039\/C9OB01159E","article-title":"Sarocladione, a Unique 5,10:8,9-diseco-steroid from the Deep-Sea-Derived Fungus Sarocladium kiliense","volume":"17","author":"Fan","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1039\/C8OB02325E","article-title":"Rearranged Ergostane-Type Natural Products: Chemistry, Biology, and Medicinal Aspects","volume":"17","author":"Duecker","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_18","first-page":"678","article-title":"A new biseco-steroid from the endolichenic fungus Sporormiella irregularis (No. 71-11-4-1)","volume":"29","author":"Li","year":"2012","journal-title":"J. Shenyang Pharm. Univ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11222","DOI":"10.1002\/anie.202101451","article-title":"Biogenesis-Guided Synthesis and Structural Revision of Sarocladione Enabled by Ruthenium-Catalyzed Endoperoxide Fragmentation","volume":"60","author":"Ning","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e170423215847","DOI":"10.2174\/1389557523666230417083143","article-title":"Biomimetic Synthesis of Biologically Active Natural Products: An Updated Review","volume":"24","author":"Shakour","year":"2024","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15070","DOI":"10.1021\/jacs.4c00098","article-title":"Incorporating Synthetic Accessibility in Drug Design: Predicting Reaction Yields of Suzuki Cross-Couplings by Leveraging AbbVie\u2019s 15-Year Parallel Library Data Set","volume":"146","author":"Raghavan","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7093","DOI":"10.1002\/anie.201101893","article-title":"Biomimetic Synthesis of 5,6-Dihydro-glaucogenin C: Construction of the Disecopregnane Skeleton by Iron (II)-Promoted Fragmentation of an \u03b1-Alkoxy Hydroperoxide","volume":"50","author":"Gui","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11656","DOI":"10.1002\/anie.201605752","article-title":"Synthesis of Strophasterol A Guided by a Proposed Biosynthesis and Innate Reactivity","volume":"55","author":"Heinze","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10911","DOI":"10.1002\/anie.201706086","article-title":"Synthesis of the Epimeric Secosteroids Strophasterols A and B","volume":"56","author":"Sato","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9211","DOI":"10.1021\/jacs.8b05070","article-title":"Total Synthesis of Aplysiasecosterol A","volume":"140","author":"Lu","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7073","DOI":"10.1002\/anie.201501749","article-title":"Aplysiasecosterol A: A 9,11-Secosteroid with an Unprecedented Tricyclic \u03b3-Diketone Structure from the Sea Hare Aplysia kurodai","volume":"54","author":"Kawamura","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Huang, L., He, C.-M., Si, C., Shi, H.-Y., and Duan, J. (2023). Nutritional, Bioactive, and Flavor Components of Giant Stropharia (Stropharia rugoso-annulata): A Review. J. Fungi, 9.","DOI":"10.3390\/jof9080792"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1021\/jacsau.3c00698","article-title":"Bioinspired Two-Phase Synthesis of Gibbosterol A","volume":"4","author":"Ning","year":"2024","journal-title":"JACS Au"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"116501","DOI":"10.1016\/j.ejmech.2024.116501","article-title":"Macrocyclization Strategy for Improving Candidate Profiles in Medicinal Chemistry","volume":"272","author":"Darlami","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"760","DOI":"10.2174\/156802611795165098","article-title":"The Significance of Chirality in Drug Design and Development","volume":"11","author":"Brooks","year":"2011","journal-title":"Curr. Top. Med. Chem."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/24\/1\/48\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T11:32:45Z","timestamp":1768908765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/24\/1\/48"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["md24010048"],"URL":"https:\/\/doi.org\/10.3390\/md24010048","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}