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To address this, a rational structure\u2010based design was employed, focusing on the under\u2010explored C\u20107 position. Methoxyamination of limonin yielded a novel derivative, limonin\u20107\u2010methoxime. Comprehensive \u00b9H and \u00b9\u00b3C NMR spectroscopy confirmed its structure, and the modification markedly improved aqueous solubility. Cytotoxicity assessment across three human adenocarcinoma cell lines (MCF\u20107, HT\u201029, LNCaP) showed that both limonin\u20107\u2010methoxime and the natural analog obakunone exerted measurable, albeit moderate, activity. They exhibited the strongest effect against LNCaP prostate cancer cells, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 249.35 and 236.15\u2009\u03bcM, respectively. Mechanistic studies indicated that both compounds were associated with cell cycle arrest and the activation of caspase\u20103\u2010mediated apoptosis in LNCaP cells. Collectively, this work validates C\u20107 functionalization as an effective strategy to enhance the drug\u2010like properties of limonoids. It delivers a structurally optimized lead compound and provides a foundation for further development aimed at improving its antitumor potency.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70210","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T05:41:56Z","timestamp":1771393316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Natural Limonoids to a Rationally Designed Derivative: Facilitating the Study of Anti\u2010Adenocarcinoma Potential and Mechanisms Through Solubility Enhancement"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8734-9923","authenticated-orcid":false,"given":"Juan","family":"Guo","sequence":"first","affiliation":[{"name":"College of Food Science Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"Luo","sequence":"additional","affiliation":[{"name":"College of Food Science Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexin","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Food Science Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinlai","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Food Science Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongmei","family":"Li","sequence":"additional","affiliation":[{"name":"College of Food Science Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yushi","family":"Gong","sequence":"additional","affiliation":[{"name":"College of Food Science Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongguang","family":"Bi","sequence":"additional","affiliation":[{"name":"College of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Advanced Drug Delivery Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huilin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2024.05.002"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12122655"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-024-10172-z"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12010201"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prenap.2025.100287"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2024.189241"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-071715-051004"},{"key":"e_1_2_8_9_1","first-page":"94","article-title":"A Brief Phytochemical Investigation and Pharmacological Uses of Citrus Seed\u2010a Review","volume":"1","author":"Rahman M. 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