Synthesis and bioactivity evaluation of pachymic acid derivatives as potential cytotoxic agents

Abstract

Pachymic acid, a well-known natural lanostane-type triterpenoid, exhibits various pharmacological properties. In this study, 18 derivatives of pachymic acid were synthesized by modifying their molecular structures and evaluated for their anticancer activity against two human cancer cell lines using the CCK-8 assay. Structure-activity relationship studies according to the in vitro cytotoxicity unexpectedly found one promising derivative A17 (namely tumulosic acid, also found in Poria cocos ), which had stronger anti-proliferative activity than the positive drug cisplatin against HepG2 and HSC-2 cell lines with IC 50 values of 7.36 ± 0.98 and 2.50 ± 0.15 μM, respectively. Further pharmacological analysis demonstrated that A17 induced HSC-2 cell cycle arrest at the S phase, cell apoptosis, and autophagy. Western blotting confirmed the regulatory effects of A17 on cell cycle arrest-, apoptosis-, and autophagy-related proteins expression. In addition, A17 regulated the AKT and AMPK pathways in HSC-2 cells. These results demonstrated that A17 possesses great potential as an anticancer agent. Graphical Abstract

Two new lanostanoid glycosides isolated from a Kenyan polypore Fomitopsis carnea

“…The introduction of a hydroxy group at C-2 rendered forpinioside C ( 2 ) inactive in antimicrobial assays compared to forpinioside B ( 1 ), however; both compounds were not active in the cytotoxicity assay. Recent structure–activity relationship (SAR) studies have indicated a key role played by the hydroxy group at C-3 in cytotoxic effects of lanostane triterpenoids [ 23 , 36 ]. According to a study by Wang et al (2023) [ 36 ], synthetic derivatives of pachymic acid demonstrated moderate to high potency against cancer cells in the presence of a 3-OH group.…”

“…Recent structure–activity relationship (SAR) studies have indicated a key role played by the hydroxy group at C-3 in cytotoxic effects of lanostane triterpenoids [ 23 , 36 ]. According to a study by Wang et al (2023) [ 36 ], synthetic derivatives of pachymic acid demonstrated moderate to high potency against cancer cells in the presence of a 3-OH group. Notably, hydrolysis of the C3-acetoxy group in pachymic acid to tumulosic acid increased the activity of the compound compared to the positive control (cisplatin), in some instances [ 36 ].…”

“…According to a study by Wang et al (2023) [ 36 ], synthetic derivatives of pachymic acid demonstrated moderate to high potency against cancer cells in the presence of a 3-OH group. Notably, hydrolysis of the C3-acetoxy group in pachymic acid to tumulosic acid increased the activity of the compound compared to the positive control (cisplatin), in some instances [ 36 ]. Concomitantly, the oxidation of the hydroxy group at C-3 into a ketone moiety diminished the activity [ 31 ].…”

“…Intriguingly, other compounds lacking the hydroxy group at C-16 were inactive, suggesting the probable role played by a 16-OH in inducing cytotoxicity. In addition, another study demonstrated that a lanostanoid glycoside derivative with a glucosyl ester at the C-21 carboxylic acid group was active in a cytotoxic activity assay, whereas the galactosyl ester counterpart was inactive [ 36 ]. Similarly, the carboxylic acid group at C-21 was shown to be a key player in lanostane triterpenoid cytotoxicity; increased activity was demonstrated either by its esterification with glucose or by its reduction into a hydroxymethylene group unlike its presence as a free carboxylic acid moiety [ 23 ].…”