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The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H<jats:sub>2<\/jats:sub>O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in<jats:italic>ex vivo<\/jats:italic>rat plasma and liver microsome and<jats:italic>in vivo<\/jats:italic>beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12\u2009mg\/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD<jats:sub>50<\/jats:sub>of acacetin prodrug was 721\u2009mg\/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.<\/jats:p>","DOI":"10.1038\/srep25743","type":"journal-article","created":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T09:18:41Z","timestamp":1462871921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs"],"prefix":"10.1038","volume":"6","author":[{"given":"Hui","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man-Wen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Sheng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Ying","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gui-Rong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,5,10]]},"reference":[{"key":"BFsrep25743_CR1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1161\/CIRCULATIONAHA.105.595140","volume":"114","author":"Y Miyasaka","year":"2006","unstructured":"Miyasaka, Y. et al. 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