Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo

Abstract

Activated hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in the injured liver and the key mediators of liver fibrosis; they also promote the progression of hepatocellular carcinoma (HCC). In the acidic extracellular microenvironment of HCC, HSCs are activated to promote the migration of HCC cells. It is worth attempting to alter the weak acidic microenvironment to promote activated HSC apoptosis to treat liver fibrosis and liver cancer. In the present study, a series of novel OA-amino acids analogues were designed and synthesized to introduce different amino acids in the 3-hydroxyl of OA using the ester condensation reaction to enhance hydrophilicity, alkalinity, and biological activity. We found that OA-lysine derivative (3g) could improve the hydrophilic of OA and induce HSCs apoptosis via inducing MMP depolarization and increasing intracellular Ca2+ levels. Additionally, 3g displayed a better hepatoprotective effect than OA (20 mg/kg, intragastric administration) against the acute liver injury induced by carbon tetrachloride (CCl4) in mice. The results suggested that basic amino acids (lysine) could effectively enhance OA’s hydrophilicity, alkalinity, and hepatoprotective activity in vitro and in vivo, which might be likely associated with increasing bioavailability and altering an extracellular weak acidic microenvironment with further verification. Therefore, the OA-lysine derivative (3g) has the potential to be developed as an agent with hepatoprotective activity.

Synthesis and cytotoxicity of 3-amino-glycyrrhetinic acid derivatives

“…Their absolute configuration at C-3 was deduced from their 1 H NMR spectra [coupling constant H-C (2)-H-C (3) and 2D-NOESY-NMR] as well as previous data reported in literature [26][27][28][29] . This reduction was not completely stereo-selective, but the epimers of opposite configuration at C-3 were only formed in minor amounts and could not be isolated [30][31][32][33][34] .…”

Amino-Acid-Conjugated Natural Compounds: Aims, Designs and Results

“…Oleanolic acid ( Figure 16 ) is a pentacyclic triterpenoid that can be found in a variety of foods and medicinal plants [ 92 , 93 ]. Oleanolic acid is widely known for its hepatoprotective properties in the treatment of acute chemical-induced liver injury, chronic liver fibrosis and cirrhosis [ 94 , 95 , 96 ]. Oleanolic acid showed biological activity against H1N1 virus infection in MDCK cells by disrupting the link between the viral protein and its receptors, preventing the virus’ attachment to the host cells [ 97 ].…”

“…To improve the hydrophilicity, alkalinity and biological activity of oleanolic acid, a variety of novel oleanolic acid–amino acid conjugates were synthesised using the ester condensation technique to incorporate different amino acids into the 3-hydroxyl of oleanolic acid [ 96 ]. These conjugates were produced to investigate their activity against HCCs and breast cancer cell lines [ 98 ].…”

“…In DCM, EDCI/DMAP was used to facilitate the process of ester condensation. The protective group was then deprotected using Pd(OH) 2 /C at the same time [ 96 ].…”

Development and Evaluation of Oleanolic Acid Dosage Forms and Its Derivatives

“…In addition, Yu et al [ 17 ] designed and synthesized two kinds of OA prodrugs that have obvious protective effect on CCl4-induced liver injury in mice, and the prodrugs improved the safety and efficacy of the parent drug. What is more, some derivatives of OA enhanced the hepatoprotective effects, such as nanosuspensions [ 1 ] and oleanolic acid-amino acids derivatives [ 18 ].…”