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As a result, 20\u2005derivatives were synthesized for bioactivity evaluation. Consequently, lung cell protective effects of (\u00b1)\u2010millpuline\u2005A and compound\n                    <jats:bold>B13\u2009a<\/jats:bold>\n                    were revealed for the first time and the crucial role of stereoconfiguration of the cyclobutane moiety in their protective effects against NNK in normal lung cells was demonstrated. Moreover, through target prediction and experimental verification in MLE\u201012\u2005cells, SRC was determined to be the target of (\u00b1)\u2010millpuline\u2005A regarding its protective effect in NNK\u2010induced lung cell injury. Results from RT\u2010Q\u2010PCR and HTRF experiments verified that (\u00b1)\u2010millpuline\u2005A could repress SRC activity through a transcriptional mechanism but not acting as an inhibitor to directly bind to and thereby inhibit SRC protein. The results in this paper are informative for the further development of visible light\u2010catalyzed cycloaddition of flavonoids and lay a scientific foundation for understanding the bioactivity and underlying mechanism of (\u00b1)\u2010millpuline\u2005A and other structurally similar natural skeletons.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202300219","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T22:45:45Z","timestamp":1694645145000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, Synthesis of (\u00b1)\u2010Millpuline\u2005A, and Biological Evaluation for the Lung Cell Protective Effects through SRC"],"prefix":"10.1002","volume":"18","author":[{"given":"Heng","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Materia Medica Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning province Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City Shenyang Pharmaceutical University  Shenyang 110016 P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Materia Medica Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning province Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City Shenyang Pharmaceutical University  Shenyang 110016 P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Materia Medica Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning province Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City Shenyang Pharmaceutical University  Shenyang 110016 P.R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,27]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9QO00678H"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153245"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00837"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c01841"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202101104"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16283-9"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.1c00290"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201901143"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.9b02968"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b04643"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202100288"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201814089"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.9b01273"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja903732v"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c01413"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201501176"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.35.23"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/a902661d"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6MD00085A"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-18-0750"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210091"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202300219","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202300219","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202300219","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:40:17Z","timestamp":1791596417000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202300219"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,27]]},"references-count":21,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2023,10,17]]}},"alternative-id":["10.1002\/cmdc.202300219"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202300219","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,27]]},"assertion":[{"value":"2023-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202300219"}}