Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

Waltenberger, Birgit; Atanasov, Atanas G.; Heiss, Elke H.; Bernhard, David; Rollinger, Judith M.; Breuss, Johannes M.; Schuster, Daniela; Bauer, Rudolf; Kopp, Brigitte; Franz, Chlodwig; Bochkov, Valery N.; Mihovilovic, Marko D.; Dirsch, Verena M.; Stuppner, Hermann

doi:10.1007/s00706-015-1653-y

Cited by 24 publications

(17 citation statements)

References 65 publications

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“…These results showed that the affinity of tocotrie-nol analogues to microsomal prostaglandin E 2 synthase-1 most probably contributes to the anti-inflammatory potential of this class of derivatives. [8], a comprehensive in silico pharmacophorebased virtual screening of T3 derivatives isolated from Garcinia amplexicaulis Vieill. ex Pierre (Clusiaceae) [9] was performed.…”

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confidence: 99%

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

et al. 2016

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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.

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confidence: 99%

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

et al. 2016

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“…Preparative HPLC was carried out on a Phenomenex Luna reversed-phase column (10 µm C18(2) phase, 100 A; 250 mm × 21.20 mm ID, (Phenomenex, Aschaffenburg, Germany), and separations were performed using a Shimadzu LC-8A device (SIL-10AP autosampler, SPD-20 detector, and FRC-10A fraction collector (Shimadzu Österreich, Korneuburg, Austria). NMR spectra were recorded from CDCl 3 or DMSO-d 6 A round bottomed flask was charged with 3,4,5-trimethoxybenzaldehyde (25 g, 127.4 mmol, 1 equiv.) under argon atmosphere.…”

Section: General Informationmentioning

confidence: 99%

“…Natural products are still considered an attractive source of biologically and pharmacologically active compounds [5]. Within a recently conducted multi-disciplinary project on the identification of natural products with anti-inflammatory activity [6], in particular, naturally occurring lignans were quite early identified to exert various kinds of biological activity [7]. As an example, the Edelweiss-derived compound leoligin 29 (Figure 1) inhibits inflammation and selective cell proliferation in vitro and in vivo suggesting its use for the treatment of vein graft disease [8].…”

Section: Introductionmentioning

confidence: 99%

“…A purely synthetic pathway would allow as well the preparation of 5-methoxyleoligin derivatives for creating a compound library of derivatives for medicinal chemistry investigations. Hence, within a multi-disciplinary project on the identification of natural products with anti-inflammatory activity [6], developing a fast, high yielding, and modular chemical synthesis of 5-methoxyleoligin and leoligin was tackled. Although there are various lignan syntheses in the scientific literature [11][12][13][14][15] delivering scaffolds with the correct absolute configuration in enantiomerically pure form, 5-methoxyleoligin was never a target of one of these syntheses and was not obtained synthetically so far.…”

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter

et al. 2020

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5-Methoxyleoligin and leoligin are natural occurring lignans derived from Edelweiss (Leontopodium nivale ssp. alpinum), displaying potent pro-angiogenic and pro-arteriogenic activity. Cholesterol efflux from macrophages is associated with reverse cholesterol transport which inhibits the development of cardiovascular disease. Within this study, we developed a modular and stereoselective total synthesis of 5-methoxyleoligin which can be readily used to prepare a novel compound library of related analogs. The target 5-methoxyleoligin was synthesized exploiting a recently disclosed modular route, which allows also rapid synthesis of analogous compounds. All obtained products were tested towards macrophage cholesterol efflux enhancement and the performance was compared to the parent compound leoligin. It was found that variation on the aryl moiety in 2-position of the furan ring allows optimization of the activity profile, whereas the ester-functionality does not tolerate significant alterations.

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“…alpinum, is reported to influence cholesterol metabolism via cholesteryl ester transfer protein (CETP), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) [13][14][15], and is thus an interesting candidate for FXR modulation. In context of an interdisciplinary research program [16] exploiting natural compound isolates towards new potential drug leads [17], we established a stereoselective synthetic route for the generation of a compound library based on the leoligin core structure [18]. In order to identify potential and novel FXR agonists, we utilized FXR specific pharmacophore models [19] to screen a database of leoligin structural analogs.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport

et al. 2020

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The ligand-activated farnesoid X receptor is an emerging therapeutic target for the development of drugs against metabolic syndrome-related diseases. In this context, selective bile acid receptor modulators represent a novel concept for drug development. Selective bile acid receptor modulators act in a target gene- or tissue-specific way and are therefore considered less likely to elicit unwanted side effects. Based on leoligin, a lignan-type secondary plant metabolite from the alpine plant Leontopodium nivale ssp. alpinum, 168 synthesized structural analogs were screened in a farnesoid X receptor in silico pharmacophore-model. Fifty-six virtual hits were generated. These hits were tested in a cell-based farnesoid X receptor transactivation assay and yielded 7 farnesoid X receptor-activating compounds. The most active one being LT-141A, with an EC50 of 6 µM and an Emax of 4.1-fold. This analog did not activate the G protein-coupled bile acid receptor, TGR5, and the metabolic nuclear receptors retinoid X receptor α, liver X receptors α/β, and peroxisome proliferator-activated receptors β/γ. Investigation of different farnesoid X receptor target genes characterized LT-141A as selective bile acid receptor modulators. Functional studies revealed that LT-141A increased cholesterol efflux from THP-1-derived macrophages via enhanced ATP-binding cassette transporter 1 expression. Moreover, cholesterol uptake in differentiated Caco-2 cells was significantly decreased upon LT-141A treatment. In conclusion, the leoligin analog LT-141A selectively activates the nuclear receptor farnesoid X receptor and has an influence on cholesterol transport in 2 model systems.

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Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

Cited by 24 publications

References 65 publications

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

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

Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter

Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport

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