{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T19:33:24Z","timestamp":1772134404544,"version":"3.50.1"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007653","name":"Universit\u00e4tsklinikum Jena","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007653","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Naunyn-Schmiedeberg's Arch Pharmacol"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Esters have been described as bioactive chemical compounds. However, the presence of an ester as a functional group is often associated with hydrolytic liability. Therefore, it is often unclear whether esters serve as pro-drugs and are rather converted into bioactive drugs in cells. The small molecule atraric acid (AA) has an ester group and had been identified as the first natural androgen receptor antagonist that inhibits prostate cancer cell growth and induces cellular senescence in cancer cells. Based on the presence of the ester group, it is unclear whether AA is a prodrug being hydrolyzed to generate the bioactive compound intracellularly. Here, we addressed this issue by synthesizing novel compounds for which the ester group has been replaced by a stable isoster. To replace the methylester group of atraric acid, a ketone with a propanoyl side chain and a <jats:italic>N<\/jats:italic>-methoxy-<jats:italic>N<\/jats:italic>-methyl-amide derivative were synthesized. Functional assays suggest that both non-ester atraric acid derivatives are bioactive in inducing cellular senescence. Treatment of human prostate cancer cells with these compounds suggest that both inhibit cell growth and induce cellular senescence in a dose-dependent manner. This was observed in two different human prostate cancer cell lines that serve as model systems for androgen-sensitive and castration-resistant prostate cancer, respectively. Computational modeling suggests that these two compounds bind to the androgen receptor ligand binding domain to similar receptor residues as AA. Thus, the data suggest that replacing the ester of AA by a ketone with a propanoyl group or by the <jats:italic>N<\/jats:italic>-methoxy-<jats:italic>N<\/jats:italic>-methyl-amide group the bioactivity as an androgen receptor antagonist is retained.<\/jats:p>","DOI":"10.1007\/s00210-025-03989-0","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T07:50:49Z","timestamp":1741765849000},"page":"11803-11819","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The bioactivity of atraric acid as an inducer of cellular senescence in prostate cancer cells is retained by lipophilic derivatives"],"prefix":"10.1007","volume":"398","author":[{"given":"Adina Asara","family":"Baniahmad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Golnaz","family":"Atri Roozbahani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aria","family":"Baniahmad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"issue":"9","key":"3989_CR1","doi-asserted-by":"publisher","first-page":"a030452","DOI":"10.1101\/cshperspect.a030452","volume":"7","author":"C Dai","year":"2017","unstructured":"Dai C, Heemers H, Sharifi N (2017) Androgen signaling in prostate cancer. 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