Nikolaus H. Fischer

Inhibition of NF-κB-mediated transcription and induction of apoptosis by melampolides and repandolides

PurposeNuclear factor-κB (NF-κB) plays a crucial role in the regulation of inflammatory processes, cell proliferation, and apoptosis. Blocking NF-κB signaling may represent a therapeutic strategy in cancer and inflammation therapy. The aim of this study was to investigate the effects of sesquiterpenes isolated from Asteraceae, namely melampolides (enhydrin, tetraludin A) and repandolides (repandins A, B, D and E) on the activation of NF-κB, cell growth of cancer cells, cell cycle progression and apoptosis. In addition, their effects on the activity of cyclooxygenase-2 (COX-2) enzyme were also evaluated.MethodsCell-based reporter gene assay was conducted in SW1353 cells. COX-2 enzyme activity and cell growth inhibition was determined by enzyme immunoassay and MTT assay respectively. Cell cycle analysis was carried out by flow cytometry and apoptosis was observed by DAPI staining assay.ResultsIn SW1353 cells, transcription mediated by NF-κB was inhibited by enhydrin, tetraludin A and repandins A, B, D and E, while Sp-1 mediated transcription was not affected. COX-2 enzyme activity was inhibited by enhydrin, repandin A and E, but not by tetraludin A, repandin B and D. These compounds were effective in inhibiting the growth of a panel of human tumor cell lines in a concentration-dependent manner. Cell cycle analysis and DAPI staining indicated cell cycle arrest in G2/M phase and induction of apoptosis.ConclusionsEnhydrin, tetraludin A and repandins A, B, D and E inhibited tumor cell growth and induced cell cycle arrest and apoptosis. These effects may be related to inhibition of NF-B activation.

Neolignans from North American Magnolia Species with Cyclooxygenase 2 Inhibitory Activity

Objectives:Based upon reported ethnomedicinal use by Native Americans, extracts and pure isolates from leaves and seeds of Magnolia grandiflora, M. virginiana, M. acuminata and M. macrophylla, all native to the Southeastern United States, were investigated for their anti-inflammatory potential against cyclooxygenase 2 (COX-2).Material and methods:The extracts and pure compounds from Magnolia species were tested for their production of prostaglandin E2 (PGE2) using a mouse macrophage (RAW 264.7) assay where cells were stimulated by lipopolysaccharide.Results:Leaf extracts were moderately active (44–58% inhibition at 50xa0μg/ml) whereas seed extracts showed significant activity of 54–88% inhibition, respectively. In the seed extract of M. grandiflora, honokiol, magnolol and 4’-O-methylhonokiol strongly inhibited COX-2 (IC50: 1.2–2.0xa0μg/ml), 3-O-methylmagnolol was moderately active while a new compound was inactive towards COX-2. The neolignans were not cytotoxic to macrophages (RAW 264.7) and kidney fibroblast (VERO) cells in vitro.Conclusions:The results indicate that the reported ethnomedicinal use of the investigated Magnolia species is in agreement with anti-inflammatory activity of their respective compounds.

The Ethnomedicinal Uses of Magnoliaceae from the Southeastern United States as Leads in Drug Discovery

In Asia and North America, members of the family Magnoliaceae have been and are presently used extensively in indigenous herbal medicine. Many taxa of the genus Magnolia produce lignans and sesquiterpene lactones, some with considerable in vitro bioactivities. This review focuses on selected natural products of the genus Magnolia from the southeastern United States with demonstrated biological and pharmacological properties. Ethnomedicinal data obtained from the Native Americans of the southeastern United States correlate well with the results of pharmacological investigations.

Three ginkgolide hydrates from Ginkgo biloba L.: ginkgolide A monohydrate, ginkgolide C sesquihydrate and ginkgolide J dihydrate, all determined at 120 K

A low-temperature structure of ginkgolide A monohydrate, (1R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11aS)-3-(1,1-dimethylethyl)-hexahydro-4,7b-dihydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3,2:3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione monohydrate, C(20)H(24)O(9) x H(2)O, obtained from Mo K alpha data, is a factor of three more precise than the previous room-temperature determination. A refinement of the ginkgolide A monohydrate structure with Cu K alpha data has allowed the assignment of the absolute configuration of the series of compounds. Ginkgolide C sesquihydrate, (1S,2R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11S,11aR)-3-(1,1-dimethylethyl)-hexahydro-2,4,7b,11-tetrahydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3,2:3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione sesquihydrate, C(20)H(24)O(11) x 1.5H(2)O, has two independent diterpene molecules, both of which exhibit intramolecular hydrogen bonding between OH groups. Ginkgolide J dihydrate, (1S,2R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11aS)-3-(1,1-dimethylethyl)-hexahydro-2,4,7b-trihydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3,2:3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione dihydrate, C(20)H(24)O(10) x 2H(2)O, has the same basic skeleton as the other ginkgolides, with its three OH groups having the same configurations as those in ginkgolide C. The conformations of the six five-membered rings are quite similar across ginkgolides A-C and J, except for the A and F rings of ginkgolide A.

Two stereoisomeric pentacyclic oxin­dole alkaloids from Uncaria tomentosa: uncarine C and uncarine E

The chloroxadform solvate of uncarine C (pteropodine), (1′S,3R,4′aS,5′aS,10′aS)-1,2,5′,5′a,7′,8′,10′,10′a-octaxadhydro-1′-methyl-2-oxospiroxad[3H-indole-3,6′(4′aH)-[1H]xadpyranoxad[3,4-f]indolizine]-4′-carboxylxadic acid methyl ester, C21H24N2O4·CHCl3, has an absolute configuration with the spiro C atom in the R configuration. Its epimer at the spiro C atom, uncarine E (isopteropodine), (1′S,3S,4′aS,5′aS,10′aS)-1,2,5′,5′a,7′,8′,10′,10′a-octahydro-1′-methyl-2-oxospiro[3H-indole-3,6′(4′aH)-[1H]pyrano[3,4-f]indolizine]-4′-carboxylic acid methyl ester, C21H24N2O4, has Z′ = 3, with no solvent. Both form intermolecular hydrogen bonds involving only the oxxadindole, with N⋯O distances in the range 2.759u2005(4)–2.894u2005(5)u2005A.

Ceratiolin from Ceratiola ericoides

The title compound, 3-phenyl-1-(2,4,5-trihydroxy-3,5-dimethyl-6-oxo-1,5-cyclohexadienyl)-1-propanone, was confirmed to be a dihydrochalcone containing a fully substituted cyclohexadienone ring. This ring has a flattened half-chair conformation, with the dione C atom 0.203 (1) A out of the diene plane and the tetrahedral C atom 0.184 (1) A to the opposite side of the plane. The hydroxy substituent on the tetrahedral C atom forms an intramolecular hydrogen bond to the carbonyl O atom of the cyclohexadienone, having an O...O distance of 2.658 (1) A and an angle at H of 116 (2) o

8-Desacetoxy-11βH,13-dihydroperoxyferolide, a Sesquiterpene Lactone Hydroperoxide

The γ-lactone of C 15 H 22 O 5 has an envelope conformation with the β-carbon at the flap. The hydroperoxy group is disordered with 92% R configuration and 8% S configuration at the chiral center to which it is bonded. The O-O distance for the major configuration is 1.463(3)A. Intermolecular hydrogen bonding exists between the hydroperoxy group and the carbonyl oxygen, with the major configuration having an O.. .O distance of 2.742(3)A.