Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo

Abstract

Betulin is a pharmacologically active triterpenoid found in the bark of the birch tree (Betula sp. L.). Betulin and betulinic acid are structurally related to anti-inflammatory steroids, but little is known about their potential anti-inflammatory properties. In the present study, the inflammatory gene expression and the anti-inflammatory properties of betulin, betulinic acid, and 16 semisynthetic betulin derivatives were investigated. Betulin derivatives 3, 4, and 5 selectively inhibited the expression of the inducible nitric oxide synthase (iNOS) in a post-transcriptional manner. They also inhibited nitric oxide (NO) production but had no effect on the other inflammatory factors studied. More interestingly, a new anti-inflammatory betulin derivative 9 with a wide-spectrum anti-inflammatory activity was discovered. Compound 9 was found to suppress the expression of cytokines interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), as well as that of prostaglandin synthase-2 (COX-2) in addition to iNOS. The in vivo anti-inflammatory effect of compound 9 was indicated via significant suppression of the carrageenan-induced paw inflammation in mice. The results show, for the first time, that the pyrazole-fused betulin derivative (9) and related compounds have anti-inflammatory properties that could be utilized in drug development.

Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential

“…What is more, BE derivatives were proven to hold anti-inflammatory activity by selective inhibition of the inducible NOS in a post-transcriptional manner, alongside with nitric oxide production (Laavola et al 2016). Some analogues also display anti-plasmodial, antibacterial and anti-HPV type 11 activity (Kazakova et al 2010;Chue et al 2011;Banzouzi et al 2015).…”

Effective synthesis of novel furan-fused pentacyclic triterpenoids via anionic 5-exo dig cyclization of 2-alkynyl-3-oxotriterpene acids

“…The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 with hexane/EtOAc (30:1) as an eluent to give a final compound: 14a-g, 17 Methyl 2α-(3,4,5-trimethoxyphenylpropynyl)-3-oxolup-20(29)en-28-oate (14f) 74 (s, 3H, H-30), 1.25, 1.14, 1.03,1.01, 0.88 (all s, 3H each, H-23-H-27). 13 C 5'-(3,4,5-trimethoxybenzyl)furano[3,2-b]lup-20(29)-en-28-oate (15f 71 (s, 3H, H-30 compound 11a-13a, 15a-f, 18a or 20a (0.4 mmol) in DMF (3 mL).…”

“…[9][10][11][12][13][14][15][16][17][18] The biological activity of triterpenoid heterocycles are promising and many of them have been studied as antitumor, [9][10][11][12][13] antiosteoporosis, 14,15 antiinflammatory 16 and antileishmanial agents. 17,18 Among this group of potentially biologically active compounds, furan triterpenoid derivatives have not been reported in the literature. Meanwhile, polysubstituted furans represent an important class of oxygen heterocycles and occur as structural moieties in many natural products and pharmaceutically important substances.…”

Effective Synthesis of a Novel Tetrahydrofuran Containing Triterpenoid: 5′(Z)-Benzylidene-tetrahydrofurano[3,2-b]lup-20(29)-en-28-oate

“…In the synthesis of numerous derivatives of betulinic acid, directed at enhancing its biological potential, particular emphasis is focused on the approaches aimed at constructing of various types of heterocyclic fragments at triterpenoid core [5]. The ketone carbonyl at C-3 of betulinic acid was utilized in syntheses of various fused heterocycles at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, benzopyrazine, pyridine, indole, and pyrazole rings [5][6][7][8][9]. These triterpenoid derivatives modified with heterocyclic rings attached to the A-ring of the triterpene have shown antitumor, anti-inflammatory and leishmanicidal activities.…”