Synthesis and biological evaluation of nitrate-oleanolic acid hybrids as inhibitors of HepG2 cell apoptosis

To find novel antihepatitis drugs, a series of nitrate-oleanolic acid (OA) hybrids (10a, 10b, 11a− 11e and 12a−12c) were designed and synthesized on the basis of previous studies using OA as lead compound, which is widely found in natural plants and liver-specific metabolism.  In the present study, ten novel NO-releasing derivatives of OA were synthesized by connecting nitrate to the OA-3-OH through varying lengths of linkers containing antioxidants which were designed to increase the ability of these target compounds to scavenge free radicals.  The structures of these objective compounds were determined by IR, MS, ¹H NMR and elemental analysis.  Their protective effects on anti-Fas mediated HepG2 cell apoptosis were in vitro evaluated by LDH assay.  Compound 12a is the most potent inhibitor.  Its effect on anti-Fas mediated HepG2 cell apoptosis and amount of NO-releasing in vitro are similar to those of positive control NCX-1000.