{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:57:02Z","timestamp":1790686622131,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22167013"],"award-info":[{"award-number":["22167013"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["22167013"],"award-info":[{"award-number":["22167013"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cephalotaxine (1) is a parent compound within the cephalotaxine alkaloids class mainly derived from Cephalotaxus plants. In this study, by coupling 1 with cinnamic acid, 17 novel cephalotaxine-cinnamic acid derivatives (S1\u2013S17) were designed and synthesized to enhance their anti-tumor efficacy. Among them, S10 showed the strongest cytotoxic activity against Huh7 cells, with the IC50 values of 9.3 and 5.9 \u03bcM after 24 h and 48 h, respectively, which were 21 and 32 times more potent than those of 1. In addition, compared with those against AML-12 cells, the proliferation inhibition rates of S10 against Huh7 cells were 5.0-fold lower, indicating a certain therapeutic window. Network pharmacology screening results indicate that S10 may exert regulatory effects closely related to cell migration and apoptosis through pathways such as PI3K\/AKT. Molecular docking showed that S10 could effectively bind to the key targets PI3K and AKT. And the Western blot experiment results confirm that S10 could downregulate the expression of p-PI3K and p-AKT at the protein level while keeping total PI3K and AKT unchanged. Notably, S10 may regulate liver cancer cells by inhibiting the PI3K\/AKT signaling pathway. Mechanistically, S10 induces S cycle arrest, reduces mitochondrial membrane potential, induces apoptosis, and inhibits migration and invasion. Overall, we reported S10 as a promising lead compound for the treatment of liver cancer.<\/jats:p>","DOI":"10.3390\/molecules31193478","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:09:25Z","timestamp":1790683765000},"page":"3478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Evaluation of Novel Cephalotaxine-Cinnamic Acid Derivatives Against Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"31","author":[{"given":"Wenxing","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"},{"name":"Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Yiming","family":"Qian","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"},{"name":"Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Research and Development of Natural Product from Li Folk Medicine of Hainan Province, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 572829, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yang","family":"Hui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"},{"name":"Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Haofu","family":"Dai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Research and Development of Natural Product from Li Folk Medicine of Hainan Province, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 572829, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"},{"name":"Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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