Citation: Xue-Yuan Jin, Shi-Yong Fan, Hong-Wu Li, Wei-Guo Shi, Wei Chen, Hui-Fen Wang, Bo-Hua Zhong. Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both NO carrier and targeting ligand[J]. Chinese Chemical Letters, ;2014, 25(05): 787-790. doi: 10.1016/j.cclet.2014.04.001 shu

Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both NO carrier and targeting ligand

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a Chinese PLA General Hospital & Chinese PLA Medical School, Beijing 100853, China;
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b Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China

Corresponding author: Hui-Fen Wang, Bo-Hua Zhong,
Received Date: 6 January 2014
Available Online: 24 March 2014
Fund Project: National Natural Science Foundation of China (Nos. 30572220 and 30972626). (863)

Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both the NO carrier and targeting ligand were designed and synthesized by direct nitration of the hydroxyl group in bile acids or the 3-O-hydroxyl alkyl derivatives, with the intact 24-COOH being preserved for hepatocyte specific recognition. Preliminary biological evaluation revealed that oral administrated targeted conjugates could protect mice against acute liver damage induced by acetaminophen or carbon tetrachloride. The nitrate level in the liver significantly increased after oral administration of 1e while nitrate level in the blood did not significantly change. Co-administration of ursodeoxycholic acid (UDCA) significantly antagonized the increase of nitrate in the liver resulted by administration of 1e.
- Liver-specific,
- Nitric oxide releasing drugs,
- Hepatoprotective activity,
- Bile acid
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  [10] Data for new compounds. 1a: Yield 73%. Mp: 221-223 ℃; ¹H NMR (400 MHz, DMSO-d₆): δ 11.93 (s, 1H), 5.29 (s, 1H) 5.07 (s, 1H), 4.79 (s, 1H), 2.39-2.37 (m, 1H), 2.26-2.23 (m, 1H), 2.23-1.02 (m, 28 H), 0.81 (s, 3H). MS (FAB): m/z 542.6 (M-1). 1b: Yield 76%. Mp: 191-193 ℃; ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 5.39 (s, 1H), 5.09 (s, 1H), 3.24 (s, 1H), 1.98-0.97 (m, 23H), 0.99-0.78 (m, 11H). MS (FAB): m/z 497.7 (M-1). 1c: Yield 67%. Mp: 218-220 ℃; ¹H NMR (400 MHz, DMSO-d₆): δ 11.93 (s, 1H), 4.85 (s, 1H), 4.20-4.18 (d, 2H), 3.79 (s, 1H), 3.63 (s, 1H), 1.99-0.97 (m, 30H), 0.59 (s, 3H). MS (FAB): m/z 452.5 (M-1). 1d: Yield 62%. Mp: 186-188 ℃; ¹H NMR (400 MHz, DMSO-d6): δ 11.84 (s, 1H), 4.85 (s, 1H), 3.60- 3.57 (d, 2H), 2.24 (s, 1H), 2.02-0.97 (m, 25H), 0.94 (d, 3H, J = 6.5 Hz), 0.85 (s, 3H), 0.63 (s, 3H). MS (FAB): m/z 436.4 (M-1). 1e: Yield 47%. Mp: 185-187 ℃; ¹H NMR (400 MHz, CDCl3): δ 11.96 (s, 1H), 4.56-4.52 (t, 2H), 3.86-3.84 (d, 1H, J = 7.0 Hz), 3.48 (s, 1H), 3.34-3.32 (t, 2H), 2.25-0.87 (m, 37H), 0.62 (s, 3H). MS (FAB): m/z 508.8 (M-1). 1f: Yield 43%. Mp: 174-176 ℃; ¹H NMR (400 MHz, CDCl₃): δ 12.05 (s, 1H), 4.56-4.54 (t, 2H), 3.90-3.87 (d, 1H, J = 6.8 Hz), 3.46 (s, 1H), 3.31-3.28 (t, 2H), 2.26-1.04 (m, 27H), 0.97 (s, 3H), 0.89 (d, 3H, J = 6.4 Hz), 0.61 (s, 3H). MS (FAB): m/z 480.5 (M-1).
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