Nuclear factor-B (NF-B) and the signaling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. NF-B regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and antiapoptotic responses. In our search for NF-B inhibitors from natural resources, we identified cardamomin, 2Ј,4Ј-dihydroxy-6Ј-methoxychalcone, as an inhibitor of NF-B activation from Alpinia conchigera Griff (Zingiberaceae). In present study, we demonstrated the effect of cardamomin on NF-B activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-B reporter gene by LPS or tumor necrosis factor (TNF)-␣ in a dose-dependent manner. LPS-induced production of TNF-␣ and NO as well as expression of inducible nitric-oxide synthase and cyclooxygenase-2 was significantly suppressed by the treatment of cardamomin in RAW264.7 cells. Also, cardamomin inhibited not only LPS-induced degradation and phosphorylation of inhibitor B␣ (IB␣) but also activation of inhibitor B (IB) kinases and nuclear translocation of NF-B. Further analyses revealed that cardamomin did not directly inhibit IB kinases, but it significantly suppressed LPS-induced activation of Akt. Moreover, cardamomin suppressed transcriptional activity and phosphorylation of Ser536 of RelA/p65 subunit of NF-B. However, this compound did not inhibit LPS-induced activation of extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun NH 2 -terminal kinase, but significantly impaired activation of p38 mitogen-activated protein kinase. We also demonstrated that pretreatment of cardamomin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-␣. Together, cardamomin could be valuable candidate for the intervention of NF-B-dependent pathological condition such as inflammation.
Four ent-kaurane diterpenoids including two known, ent-7alpha,14beta-dihydroxykaur-16-en-15-one (1) and ent-18-acetoxy-7alpha-hydroxykaur-16-en-5-one (2), and two new, ent-1beta-acetoxy-7alpha,14beta-dihydroxykaur-16-en-15-one (3) and ent-18-acetoxy-7alpha,14beta-dihydroxykaur-16-en-15-one (4), were isolated from the leaves of Croton tonkinensis in a search for inhibitors of NF-kappaB activation and nitric oxide production. These ent-kauranoids inhibited LPS-induced NF-kappaB activation in murine macrophage RAW264.7 cells at IC50 values between 0.07 and 0.42 microM. Consistently, the ent-kauranoids markedly reduced LPS-induced NO production in a comparable concentration-dependent manner.
In recent years, eight tetracyclic ent-kaurane-type diterpenoids were isolated by us from the leaves of Croton tonkinensis GAGNEP. (Euphorbiaceae).1,2) In our continuing search for more bioactive compounds from this plant, six new diterpenoids 2-4, 6, 8, and 14 were isolated together with three known ent-kauranes ent-11a-acetoxy-7b,14a-dihydroxykaur-16-en-15-one (1), ent-kaur-16-en-15-one 18-oic acid (5), and ent-18-hydroxykaur-16-ene (7). The known compounds were identified by comparison of their spectroscopic data ( 1 H-, 13C-NMR) with published values. 3-5) Compounds 2-4 and 6, along with diterpenoids 9-13, which were previously isolated from C. tonkienesis, 1,2) were tested for their cytotoxicity in the brine shrimp lethality assay. This paper deals with the structure elucidation of the new compounds and the results of the brine shrimp lethality assay. Results and DiscussionCompound 2 C-NMR spectroscopic data of 2 with those of the diterpenoid 9, 1) 2 was suggested to belong to the entkaurane series. The acetyl group was assigned at C-7 (d C 73.6) on the basis of the heteronuclear multiple bond correlation (HMBC) cross-peaks ( (Table 1) and 13 C-NMR (Table 2) Six new ent-kaurane-type diterpenoids were isolated from the leaves of the endemic Vietnamese medicinal plant Croton tonkinensis GAGNEP. (Euphorbiaceae) together with three known ent-11a a-acetoxy-7b b,14a a-dihydroxykaur-16-en-15-one (1), ent-kaur-16-en-15-one 18-oic acid (5) and ent-18-hydroxykaur-16-ene (7). Their structures were determined by spectroscopic analyses to be ent-7b b-acetoxy-11a a-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-11a a-hydroxykaur-16-en-15-one (3), ent-11a a-acetoxykaur-16-en-18-oic acid (4), ent-15a a,18-dihydroxykaur-16-ene (6), ent-11a a,18-diacetoxy-7b b-hydroxykaur-16-en-15-one (8), and ent-(16S)-1a a,14a a-diacetoxy-7b b-hydroxy-17-methoxykauran-15-one (14). ent-Kaurane-type diterpenoids from Croton tonkinensis 2-4, 6, and 9-13, were tested for toxicity in the brine shrimp lethality assay. Compounds 9, 10, and 12 demonstrated significant activity, compounds 2, 3, 6, and 11 showed weak activity, and compounds 4 and 13 were inactive.
Croton tonkinensis GAGNEP. (Euphorbiaceae), commonly known as Kho sam cho la in Vietnamese, is a small plant indigenous to Northern Vietnam. In Vietnamese traditional medicine the species is used as remedies for gastric and duodenal ulcers and many other diseases.1) Recently, the antiinflammatory and cancer chemopreventive activity of C. tonkinensis extracts were discovered through its ability to inhibit the activation of the transcription factor nuclear factor kappa B (NF-kB), and the activity is assumed to be correlated with the ent-kaurane diterpenoid constituents.2) The presence of kaurane diterpenoids in the Croton species is very uncommon, although so far the ent-kauranes have been found in many plants of the genus Rabdosia (Labitae).3) Therefore further phytochemical study on the ent-kaurane diterpenoids accumulated in C. tonkinensis is necessary. Other constituents were also isolated from this plant including phytosterols, long-chain alkyl alcohols, and flavonoid glucosides. 4)In the continuation of our study, this paper deals with the isolation and structural elucidation of the four new ent-kauranetype diterpenoids 1-4 (Fig. 1).Compound 1 was isolated as an amorphous powder and its elemental composition was determined to be C 24 H 34 O 6 by the [MϩNa] ϩ peak at m/z 441.6 in the positive-ion electrospray ionization mass spectrometry (ESI-MS) and [MϩNa] ϩ peak at m/z 441.2243 in the positive-ion high-resolution (HR)-FAB-MS. The IR spectrum indicated the presence of a hydroxy (3558 cm (Table 1) and 13 C-NMR (Table 2) signals of 1 were found to be similar to those of ent-1a-acetoxy-7b,14a-dihydroxykaur-16-en-15-one (5), 2) which was isolated from the same extract, except for the presence , and H-7 and H-5 and H-9 in the nuclear Overhauser enhancement and exchange spectroscopy (NOESY) spectrum of 1 (Fig. 2) the acetoxyl groups at C-1 and C-14 were assigned to occupy an ent-a-orientation, and the hydroxyl group at C-7 an ent-b-orientation. Thus the structure of 1 was determined to be ent-1a,14a-diacetoxy-7b-hydroxykaur-16-en-15-one (Table 1) and 13 C-NMR (Table 2) data of 2 with those of 1 revealed very close agreement, showing the presence of a 20-carbon skeleton of an ent-kaurane diterpenoid together with two secondary acetoxyl groups. The main differences -1a a,14a a-diacetoxy-7b b-hydroxykaur-16-en-15-one (1), ent-1a a,7b b-diacetoxy-14a a-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-14a a-hydroxykaur-16-en-15-one (3), and ent-(16S)-18acetoxy-7b b-hydroxykauran-15-one (4) were isolated. Their structures were elucidated by spectroscopic analyses.
Leonurus heterophyllus SW. (family: Lamiaceae, syn. Labiatae) is used in Vietnamese traditional medicine for the treatment of menstruation and child delivery in gynaecology, high blood pressure, blood stasis, heart disorders, and dysentery.1) The rich distribution of bis-spirolabdane-type diterpenoids with variations of functionalities in the plants of the genus Leonurus was reported in the previous studies on chemical composition of L. persicus, 2-5) L. cardiaca, 6,7) and L. sibiricus. 8,9) Similarly, two prefuranic labdane-type diterpenoids were isolated from L. heterophyllus collected in Guangdong Province, China.10,11) However, a systematic chemical investigation on L. heterophyllus is necessary for reasons of chemotaxonomic interest. It is noteworthy that bis-spirocyclic labdane-type compounds are not confined to the Leonurus species, and so far have been found in the genera of Leonotis (Lamiaceae), 12) Marrubium (Lamiaceae), 12)Otostegia (Lamiaceae), 13) and Vitex (Verbenaceae). 14,15) In our present study, systematic extraction and isolation afforded twelve natural bis-spirolabdane-type diterpenoids (1-12), eight of which are new (3, 6-12), together with hispanone (13) and galeopsin (14). The known diterpenoids, leopersin B (1), 15-epileopersin B (2), leopersin C (4), 15-epileopersin C (5), 13 and 14 are identified on the basis of physical ([a] D ), and 1 H-and 13 C-NMR data. 2,3,16,17) Air-dried aerial parts of L. heterophyllus were extracted with MeOH by percolation at room temperature. Concentration under reduced pressure yielded an extract, which was divided into n-hexane-, ethyl acetate-and 1-BuOH-soluble parts by sequential solvent partitioning with H 2 O. Bis-spirocyclic compounds 1-12, and compounds 13 and 14 were obtained by systematic fractionation of n-hexane-soluble fraction first over silica gel, then over reversed-phase octadecyl silica (ODS) gel, followed by preparative HPLC. While compounds 3, 8, 13 and 14 were obtained in pure form, the other compounds were isolated as epimeric pairs 1/2, 4/5, 6/7, 9/10 and 11/12 at C-15 position. This phenomenon of the co-occurrence of C-15 oxygenated epimeric pairs has been frequently seen in many examples of bis-spirolabdanetype diterpenoids of the genus Leonurus. [2][3][4][5][6][7]9) Although the absolute configurations of 1-12 were not individually confirmed herein, they are probably of the same normal labdane-type diterpenoids on the basis of the co-occurrence with 13 and 14, since the formation of bis-spirotetrahydrofuranes involves only C-9 side chain. Additionally, compounds 1/2 and 4/5 were previously isolated from the same extraction fractions together with 4-b-hydroxymethylpregaleopsin, the absolute assignments of p-bromobenzoate derivative of which have been unambiguously determined by single-crystal X-ray crystallographic analysis.2) Therefore, the stereochemistry of 1-12 is suggested to be presented as in the normal series of labdane-type diterpenoids.Leoheteronone A (3) , including eight new, named leoheteronones A-E (3, 6, 8, 9, 11), 15-...
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