Synthesis, cytotoxicity and anti-inflammatory activity of rhamnose-containing ursolic and betulinic acid saponins

Abstract

Betulinic acid and ursolic acid are ubiquitous, naturally-occurring triterpenoids exhibiting various pharmacological activities including cytotoxic and anti-inflammatory activities. However, these triterpenoids display unfavorable pharmacokinetic properties as well as low aqueous solubility. It has been shown that the presence of a-L-rhamnose moieties positively modulates the anticancer activity of secondary metabolites. Herein we report the synthesis and in vitro evaluation of cytotoxic and antiinflammatory activities of a series of rhamnose-containing ursolic and betulinic acid saponins. Relying on Schmidt's normal and inverse procedures, monorhamnosides, (1/4)-linked dirhamnosides as well as branched trirhamnosides and tetrarhamnosides were synthesized in high yields with full control of stereoselectivity. A betulinic acid saponin bearing a 3-O-a-L-rhamnopyranosyl-(1/4)-a-Lrhamnopyranosyl residue was found to be a potent cytotoxic agent against human colorectal adenocarcinoma cells without damaging the healthy cells (selectivity ratio > 20) whereas rhamnosecontaining ursolic acid saponins potently inhibited NO overproduction induced by LPS-stimulated macrophages. Our results reveal that rhamnose-containing ursolic and betulinic acid saponins represent promising therapeutic agents.

Biological and Pharmacological Effects of Synthetic Saponins

“…Immune upregulation activities were majorly evaluated in quillaic-saponins, which were extensively studied for the enhancement of serum IgG production compared to GPI-0100 and QS-21 for the development of vaccine adjuvants [47][48][49]. As for immune downregulation activities, ursane-saponins were able to protect H9c2 cardiomyocytes from H 2 O 2 -induced apoptosis in a dose-dependent manner (0.02-0.5 µg/mL) through the inhibition of ROS generation and maintenance of mitochondrial membrane potential which were possibly related to the binding of Hsp90AB1 [52,89], and prevented NO overproduction induced by lipopolysaccharides (LPSs) in macrophages with EC 50 = 9.8 µM [53]; dammarane-saponins were found to be effective in reducing serum IgE levels and airway resistance in an OVA-induced asthmatic mouse model [60]. The activity of glucosidase inhibition was evaluated in oleanane-, ursane-, and furostane-type saponins.…”

“…Legault and co-workers have demonstrated that a bidesmosidic betulinic saponin 28-O-α-l-rhamnopyranosyl betulin 3β-O-α-l-rhamnopyranoside (Bi-L-RhamBet) induced lung cancer cell death through the mitochondrial electron transfer chain which induced ROS production and decreased membrane potential, leading to apoptosis and DNA fragmentation [97]. Based on the findings, Pichette and co-workers synthesized α-L -rhamnose-containing betulinic and ursolic saponins, which exhibited cytotoxicity against human colorectal adenocarcinoma cells DLD-1 (IC 50 = 5 µM) and low toxicity in human skin fibroblasts WS-1 (IC 50 > 100 µM) in dirhamnoside-bearing betulinic derivatives (25) and anti-inflammatory activity was revealed in ursolic derivatives (26) [53]. Liberek and co-workers synthesized glucosamine-and galactosamine-containing betulinic saponins, revealing that galactosamine derivative (27) exhibited high cytotoxicity in both MCF-7 breast cancer cells and HDFa normal cells (1.7 and 4.2 µM, respectively), and had no inhibition activity toward bacteria and fungi [54].…”

Biologically active compounds of plant origin in medicine

“…Saponins exhibit varied levels of anti-inflammatory activity, which is associated with their chemical structure [Gepdiremen et al 2005, Sylla et al 2019. As shown in a study conducted by Süleyman et al [2003], crude and purified saponin Hedera helix extracts were effective inhibitors of carrageenan-and cottonpellet-induced acute and chronic inflammation in rats.…”

Toxicological evaluations of betulinic acid and ursolic acid; common constituents of Houttuynia cordata used as an anthelmintic by the Naga tribes in North-east India

“…Betulinic acid (BA) is a naturally occurring pentacyclic lupane-type triterpene [13] which has been used in folk medicine for centuries [14]. It is known to possess antiviral [15], anti-malarial [16], anti-inflammatory [17], and anthelmintic activity against Caenorhabditis elegans [18].…”