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. 2019 Dec;22(12):1452-1461.
doi: 10.22038/IJBMS.2019.13991.

Synthesis and evaluation of a prodrug of 5-aminosalicylic acid for the treatment of ulcerative colitis

Yan Yan  1 , Fengling Ren  2 , Pengchong Wang  1 , Ying Sun  1 , Jianfeng Xing  1
Affiliations

Synthesis and evaluation of a prodrug of 5-aminosalicylic acid for the treatment of ulcerative colitis

Yan Yan et al. Iran J Basic Med Sci. 2019 Dec.

Abstract

Objectives: This study is aimed to design and synthesize a prodrug of 5-aminosalicylic acid and evaluate its ameliorative effect on experimental ulcerative colitis (UC).

Materials and methods: 5-Aminosalicylic acid-alanine (5-ASA-ALA) was synthesized and characterized. Its stability study was conducted in rat plasma and in the gastrointestinal tract environment, its transport characteristic was assessed using the Caco-2 cells. Its colon-targeting property was evaluated by the pharmacokinetic study, and incubation studies. A series of indicators were used to investigate its therapeutic effect on experimental colitis, including the survival rate and body weight of mice, the disease activity index (DAI), the colonic damage score and colon index, the myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), total superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) in colonic tissues.

Results: 5-ASA-ALA was barely absorbed in the Caco-2 monolayer or into the rat blood. It was remarkably stable when incubated in the upper gastrointestinal tract, while gradually hydrolyzed in the colon of rats. When orally administered to mice, 5-ASA-ALA had significantly greater therapeutic effect on colitis than the positive control.

Conclusion: 5-ASA-ALA is demonstrated to be a promising oral colon-targeting prodrug of 5-ASA and has potential application in UC treatment.

Keywords: 5-Aminosalicylic acid; Anti-inflammation; Colon targeting; Prodrug; Ulcerative colitis.

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Figures

Scheme 1
Scheme 1
A prodrug of 5-aminosalicylic (5-ASA-ALA) acid was designed and synthesized in this study. 5-aminosalicylic (5-ASA-ALA) was proved to have desirable colon-targeting property and therapeutic effect on experimental colitis when orally administrated to mice
Figure 1
Figure 1
Synthesis and characterization of 5-ASA-ALA. (a) The synthetic route of 5-ASA-ALA. (b) The 1H NMR spectrum of 5-ASA-ALA. (c) The FTIR spectrum of 5-ASA-ALA. 5-ASA-ALA, 5-aminosalicylic acid-alanine
Figure 2
Figure 2
Plasma concentration curves of 5-ASA and 5-ASA-ALA in rats. 5-ASA-ALA, 5-aminosalicylic acid-alanine; 5-ASA, 5-aminosalicylic acid. Data are means±SD, n=6
Figure 3
Figure 3
Hydrolysis rate of 5-ASA-ALA during incubation with the colon contents of rats. 5-ASA-ALA, 5-aminosalicylic acid-alanine. Data are means±SD, n=6
Figure 4
Figure 4
Percent of hydrolysis of 5-ASA-ALA in clindamycin group and control group after in vivo incubation in rats for 8 hr. 5-ASA-ALA, 5-aminosalicylic acid-alanine. Data are means±SD, n=6, **P<0.01
Figure 5
Figure 5
Effects of 5-ASA-ALA on survival rate (a) and body weight (b) of mice. The weight loss of mice in each group was recorded daily for 5 days continuouslly, the survival rate in each group was calculated at the end of the experiment. A physical mixture of 5-ASA and alanine was used as the positive control. 5-ASA-ALA, 5-aminosalicylic acid-alanine. Data are means±SD, n=12
Figure 6
Figure 6
Effects of 5-ASA-ALA on DAI of mice. After the induction of colitis, mice in each group were administered with drugs equivalent to 100 mg/kg of 5-ASA. The DAI of mice was recorded and scored daily. A physical mixture of 5-ASA and alanine was used as the positive control. 5-ASA-ALA, 5-aminosalicylic acid-alanine; DAI, disease activity index. Data are means±SD, n=12
Figure 7
Figure 7
Effects of 5-ASA-ALA on colon index and CDS of mice. (a) At the end of the experiment, all mice were sacrificed and their entire colons were excised and measured to calculate the colon index. (b) The CDS of mice in each group was scored according to the macroscopical changes of the colon. CDS, colonic damage score. ##: P<0.01 vs control group; *: P<0.05, **: P<0.01 vs TNBS group; ∆: P<0.05 vs positive control group. Data are shown as mean±SD, n=12
Figure 8
Figure 8
Effects of 5-ASA-ALA on MPO activity of mice. After treatment, the MPO activity of mice in colonic tissues was measured to evaluate the potential therapeutic effects of 5-ASA-ALA. MPO, myeloperoxidase. ##: P<0.01 vs control group; *: P<0.05, **: P<0.01 vs TNBS group; ∆∆: P<0.01 vs positive control group. Data are mean±SD, n=12
Figure 9
Figure 9
Effects of 5-ASA-ALA on levels of MDA, SOD, GSH and GSH-Px. After treatment, the MDA level (a), SOD activity (b), GSH level (c) and GSH-Px activity (d) of mice in colonic tissues were measured to evaluate the potential therapeutic effects of 5-ASA-ALA. SOD, superoxide dismutase; MDA, malondialdehyde; GSH, glutathione; GSH-Px, glutathione peroxidase. ##: P<0.01 vs control group; *: P<0.05, **: P<0.01 vs TNBS group; ∆∆: P<0.01 vs positive control group. Data are mean±SD, n=12
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