熊果酸衍生物及其醫藥組合物 / Ursolic Acid Derivative And Pharmaceutical Composition ThereofURSOLIC ACID DERIVATIVE AND PHARMACEUTICAL COMPOSITION THEREOF

專利類型

發明

專利國別 (專利申請國家)

美國

專利申請案號

12/782,395

專利證號

US 8,729,055 B2

專利獲證名稱

熊果酸衍生物及其醫藥組合物 / Ursolic Acid Derivative And Pharmaceutical Composition ThereofURSOLIC ACID DERIVATIVE AND PHARMACEUTICAL COMPOSITION THEREOF

專利所屬機關 (申請機關)

高雄醫學大學

獲證日期

2014/05/20

技術說明

由ursolic acid為原料共合成23種化合物，其中5,7-11, 20-22為新化物，23種化合物對人類膀胱癌細胞(NTUB1)之毒性分析結果，以具有C-17-COOH轉變成isopropyl ester之化合物5及C-3轉變成succinate之化合物17抗NTUB1癌細胞最強。由ursolic acid轉變為seco-化合物後23與24，其抗NTUB1 cell活性會增強。化合物5 (40 μM)及23 (20與50 μM)，或5 (20與40 μM)及23 (20與50 μM) 在NTUB1內分別培養24h or 48h，皆會增加活性氧量，但17卻不會。化合物5，或17或23經 flow cytometric分析結果可知三者經24或48時培養後，會發生細胞周期停止並有凋亡細胞增加現象。綜合以上可知5與23與NTUB1細胞培養24時後，會經由活性氧量之增加，引發G1細胞周期之停止及細胞凋亡現象。化合物5經48時培養後，會由於活性氧之增加，導致細胞周期停止於G2/M期，並有細胞凋亡現象，化合物23在NTUB1內培養48h亦會增加ROS量啟動tubulins polymerization抑制而導致G2/M期停止及凋亡。 Twenty three ursolic acid (1) derivatives 2-24 including nine new 1 derivatives 5, 7, 8, 9, 10, 11, 20, 21, and 22 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell line). Compounds 5 and 17 with an isopropyl ester moiety at C-17-COOH and a succinyl moiety at C-3-OH showed potent inhibitory effect on growth of NTUB1 cells. Compounds 23 and 24 with seco-structures prepared from 1 also showed the increase of the cytotoxicity against NTUB1 cells. Exposure of NTUB1 to 5 (40μM) and 23 (20 and 50μM) for 24 h significantly increased the production of reactive oxygen species (ROS) while exposure of NTUB1 to 5 (20 and 40 μM) and 23 (20 and 50 μM) for 48 h also significantly increased the production of ROS while exposure of cells to 17 did not increase the amount of ROS. Flow cytometric analysis exhibited that treatment of NTUB1 with 5 or 17 or 23 led to the cell cycle arrest accompanied by an increase in apoptotic cell death after 24 or 48 h.

備註

本部(發文號1100044017)同意貴校110年1月28日高醫產學字第1101100305號函申請終止維護專利。(高醫)

連絡單位 (專責單位/部門名稱)

智財保護與科技管理組

連絡電話

07-3138030

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