Novel Nitric Oxide Donor Dinitroazetidine-Coumarin Hybrids as Potent Anti-Intrahepatic Cholangiocarcinoma Agents |
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| Authors: | Zhihui Yu Mengru Li Shiqi Guo Weijie Wang Feng Qu Yulei Ma Hongrui Liu Ying Chen |
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| Affiliation: | 1.Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China; (Z.Y.); (S.G.); (W.W.); (F.Q.);2.Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China; (M.L.); (Y.M.) |
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| Abstract: | Intrahepatic cholangiocarcinoma (iCC) is a serious liver cancer threatening human health. However, there are a few chemotherapeutic drugs for the treatment of iCC in the clinic. It is extremely urgent to develop new drugs for iCC. In this study, twenty dinitroazetidine and coumarin hybrids were synthesized and evaluated anti-iCC bioactivity as a new type of nitric oxide (NO) donors. Among them, compounds 2–5 and 21 showed a higher antiproliferative activity against RBE cell lines (human intrahepatic cholangiocarcinoma cell lines) and low cytotoxicity in nontumor cells (HOSEpiC and T29). The preliminary study of pharmacology mechanism indicated that compounds 2–5 and 21 could release effective concentration of NO in RBE cell lines, which leaded to inhibit the proliferation of RBE cell lines. The research results revealed that compound 3 inhibited the proliferation of RBE cell lines by inducing apoptosis and arresting cell cycle at G2/M phase. Additionally, compound 3 had acceptable metabolic stability. Therefore, compound 3 was merited to further explore for developing a desirable NO donor lead with anti-iCC activity. |
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| Keywords: | intrahepatic cholangiocarcinoma NO donor dinitroazetidine-coumarin hybrids antitumor |
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