Semisynthetic and Natural Garcinoic Acid Isoforms as New mPGES-1 Inhibitors

Abstract

Over the last twenty years, tocotrienol analogues raised great interest because of their higher level and larger domain of biological activities when compared with tocopherols. Amongst the most promising therapeutic application, anti-inflammatory potency has been evaluated through the inhibition of various mediators of inflammation. Here, we worked on the isolation of two natural isoforms of garcinoic acid (i.e., δ and γ) from two different sources, respectively, Garcinia kola seeds and Garcinia amplexicaulis bark. We also developed semisynthetic strategies to access the other two non-natural α- and β-garcinoic acid isoforms. In the next stage of our work, microsomal prostaglandin E2 synthase was defined as a target to evaluate the anti-inflammatory potential of the four garcinoic acid isomers. Both dimethylated isoforms, β- and γ-garcinoic acid, exhibited the lowest IC50, 2.8 µM and 2.0 µM, respectively. These results showed that the affinity of tocotrienol analogues to microsomal prostaglandin E2 synthase-1 most probably contributes to the anti-inflammatory potential of this class of derivatives.

Diversity of Chromanol and Chromenol Structures and Functions: An Emerging Class of Anti-Inflammatory and Anti-Carcinogenic Agents

“…Formation of PGE 2 in LPS-stimulated monocytes was inhibited already by 300 nM d-T3-13′-COOH (Pein et al, 2018). In line with this, d-T3-13′-COOH also inhibited activity of microsomal PGE 2 synthase (by nearly 70%) at a concentration of 10 mM in a cell-free assay using microsomes of IL-1b-stimulated human lung adenocarcinoma A549 cells as an enzyme source (Alsabil et al, 2016;Pein et al, 2018). However, in Apoe -/mice fed a high fat diet with 1 mg/kg d-T3-13′-COOH for 8 weeks neither nitric oxide, PGE 2 , TXB 2 nor IL-1b concentrations in plasma were altered compared to the control group (Wallert et al, 2019).…”

Natural 6-hydroxy-chromanols and -chromenols: structural diversity, biosynthetic pathways and health implications

“…As a possible target for its anti-inammatory action, microsomal prostaglandin E 2 synthase has been identied recently. 44 The two natural (d-and g-garcinoic acid) isoforms as well as semi-synthesized band a-garcinoic acid inhibited the enzyme with IC 50 values of 6.7, 2.0, 2.8 and 7.8 mM, respectively.…”

“…[37][38][39][40][41][42] It has been detected in different amounts within the Clusiaceae family including Tovomitopsis psychotriifolia, Clusia obdeltifolia, Clusia burlemarxii, Clusia pernambucensis, Garcinia kola and together with g-garcinoic acid (31) in the bark of Garcinia amplexicaulis. 43,44 Recently, g-garcinoic acid was isolated in small amounts from the Algerian conifer Cedrus atlantica (Pinaceae). 45 A mixture of 2(Z)-d-garcinoic acid and 2(E)-d-garcinoic acid was isolated from the stem of Clusia obdeltifolia.…”

“…43 From the methanolic extract of leaves of Litchi chinensis (Sapindaceae), several d-tocotrienol derivatives with side chain and chromanol modications were isolated and investigated for their anti-cancerogenic potential. 49 Litchtocotrienols A-G (41)(42)(43)(44)(45)(46)(47) are hydroxylated at C-11 0 with R-conguration and E-F (45, 46) contain a ketone group at C-11 0 (Fig. 6).…”

“…255,260 A direct comparison of several carboxytocotrienols (tocotrienol-13 0 -COOH metabolites) from plant origin as inhibitors of microsomal PGE 2 synthase-1 revealed the following order of activity: g-garcinoic acid (31) > b-garcinoic acid (232) > d-garcinoic acid (30) > a-garcinoic acid (209); however the methylation pattern had only moderate impact. 44 Structurally related forms of d-garcinoic acid, such as d-sargachromenol (51) with a 15 0 -COOH group and a chromene ring system, showed only moderate inhibitory activity on in LPSstimulated production nitric oxide and PGE 2 in murine RAW 264.7 macrophages (IC 50 values of 82 mM and 30.2 mM, respectively); 129 however, much higher activity was observed in BV-2 microglial cells (IC 50 value for inhibition of nitric oxide production of 1.3-2.7 mM). 134, 261 As described above, 13 0 -OH metabolites have a similar anti-inammatory potential than the corresponding 13 0 -COOH.…”