Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

With many cancers showing resistance to current chemotherapies, the search for novel anti-cancer agents is attracting considerable attention. Natural flavonoids have been identified as useful leads in such programmes. However, since an in-depth understanding of the structural requirements for optimum activity is generally lacking, further research is required before the full potential of flavonoids as anti-proliferative agents can be realised. Herein a broad library of 76 methoxy and hydroxy flavones, and their 4-thio analogues, was constructed and their structure-activity relationships for anti-proliferative activity against the breast cancer cell lines MCF-7 (ER+ve), MCF-7/DX (ER+ve, anthracycline resistant) and MDA-MB-231 (ER-ve) were probed. Within this library, 42 compounds were novel, and all compounds were afforded in good yields and > 95% purity. The most promising lead compounds, specifically the novel hydroxy 4-thioflavones 15f and 16f, were further evaluated for their anti-proliferative activities against a broader range of cancer cell lines by the National Cancer Institute (NCI), USA and displayed significant growth inhibition profiles (e.g Compound-15f: MCF-7 (GI50 = 0.18 μM), T-47D (GI50 = 0.03 μM) and MDA-MB-468 (GI50 = 0.47 μM) and compound-16f: MCF-7 (GI50 = 1.46 μM), T-47D (GI50 = 1.27 μM) and MDA-MB-231 (GI50 = 1.81 μM). Overall, 15f and 16f exhibited 7-46 fold greater anti-proliferative potency than the natural flavone chrysin (2d). A systematic structure-activity relationship study against the breast cancer cell lines highlighted that free hydroxyl groups and the B-ring phenyl groups were essential for enhanced anti-proliferative activities. Substitution of the 4-C=O functionality with a 4-C=S functionality, and incorporation of electron withdrawing groups at C4’ of the B-ring phenyl, also enhanced activity. Molecular docking and mechanistic studies suggest that the anti-proliferative effects of flavones 15f and 16f are mediated via ER-independent cleavage of PARP and downregulation of GSK-3β for MCF-7 and MCF-7/DX cell lines. For the MDA-MB-231 cell line, restoration of the wild-type p53 DNA binding activity of mutant p53 tumour suppressor gene was indicated.

Coordination of nitro-thiosemicarbazones to ruthenium(II) as a strategy for anti-trypanosomal activity improvement

Complexes [RuCl(H4NO(2)Fo4M)(bipy)(dppb)]PF(6) (1), [RuCl(H4NO(2)Fo4M)(Mebipy)(dppb)]PF(6) (2), [RuCl(H4NO(2)Fo4M)(phen)(dppb)]PF(6) (3), [RuCl(H4NO(2)Ac4M)(bipy)(dppb)]PF(6) (4), [RuCl(H4NO(2)Ac4M)(Mebipy)(dppb)]PF(6) (5) and [RuCl(H4NO(2)Ac4M)(phen)(dppb)]PF(6) (6) with N(4)-methyl-4-nitrobenzalde hyde thiosemicarbazone (H4NO(2)Fo4M) and N(4)-methyl-4-nitroacetophenone thiosemicarbazone (H4NO(2) Ac4M) were obtained from [RuCl(2)(bipy)(dppb)], [RuCl(2)(Mebipy)(dppb)], and [RuCl(2)(phen)(dppb)], (dppb = 1,4-bis(diphenylphospine)butane; bipy = 2,2`-bipyridine: Mebipy = 4,4`-dimethyl-2,2`-bipyridine: phen = 1,10-phenanthroline). In all cases the thiosemicarbazone is attached to the metal center through the sulfur atom. Complexes (1-6), together with the corresponding ligands and the Ru precursors were evaluated for their ability to in vitro suppress the growth of Trypanosoma cruzi. All complexes were more active than their corresponding ligands and precursors. Complexes (1-3) and (5) revealed to be the most active among all studied compounds with ID(50) = 0.6-0.8 mu M. In all cases the association of the thiosemicarbazone with ruthenium, dppb and bipyridine or phenanthroline in one same complex proved to be an excellent strategy for activity improvement. (C) 2010 Elsevier Masson SAS. All rights reserved.

Isolation, chemical composition and anti-inflammatory activity of Copaifera langsdorffii desf. fruit peels essential oil according to successive hydrodistillations

In this study, the isolation and characterization of chemical composition of C. langsdorffii (copaiba) fruit peel volatile oil from Alfenas - MG was carried out according to successive hydrodistillations, likewise the anti-inflammatory activity was evaluated by rat paw edema model. The chemical composition of the oil was determined by GC-MS analysis. The major components were (E)-caryophyllene, germacrene B, 1,5-epoxysalvial-4(14)-ene, caryophyllene oxide and isospathulenol. The inflammatory process was inhibited in 39 +/- 6 % (p<0.05, Tukey-Kramer) by one sample of essential oil. The C. langsdorffii fruit peel is a rich source of essential oil (3.8% w/w), and due to potential industrial interest of its components this ecotype presents feasible crop seeking productivity and it could constitutes in a good alternative to the sustainable use of this specie.

Anti-inflammatory activity of essential oil from leaves of Myrciaria tenella and Calycorectes sellowianus

The GC-MS analysis revealed that the leaf essential oils of Myrciaria tenella (DC.) Berg and Calycorectes sellowianus O. Berg (Myrtaceae) were composed of 34 and 37 compounds, respectively. The main constituents of M. tenella oil were beta-caryophyllene (25.1%), and spathulenol (9.7%), while for C. sellowianus were guaiol (13.1%) and beta-caryophyllene (8.6%). The anti-inflammatory effect of both essential oils was investigated in vitro and in vivo. Both oils reduced significantly (p < 0.005) the treated neutrophils chemotaxis with 93% and 91% inhibition for M. tenella and C. sellowianus, respectively. However, in the systemic treatment with the essential oils (50 mg/kg p.o.) only the M. tenella oil was able to significantly reduce the carrageenan-induced paw edema with a similar effect to that observed for indomethacin (10 mg/kg), the positive control.

A combined X-ray and theoretical study of flavonoid compounds with anti-inflammatory activity

The structure of 7,4`-dimethoxy-3`-acetylflavone (tithonin-Ac) has been determined by X-ray diffraction and its geometry is compared with optimized geometrical parameters obtained by means of density functional theory at the B3LYP/6-311++G(d,p) level of calculation. in addition, vertical ionization potential (IPv) and acidity for tithonin-Ac and two derivatives have been also calculated. Calculations of spin densities were also performed for the radical formed by the electron abstraction of other flavones. The unpaired electron is located on C3 carbon atom (21-25%). (C) 2008 Elsevier B.V. All rights reserved.

Insights into the Molecular Requirements for the Anti-obesity Activity of a Series of CB1 Ligands

Two-dimensional and 3D quantitative structure-activity relationships studies were performed on a series of diarylpyridines that acts as cannabinoid receptor ligands by means of hologram quantitative structure-activity relationships and comparative molecular field analysis methods. The quantitative structure-activity relationships models were built using a data set of 52 CB1 ligands that can be used as anti-obesity agents. Significant correlation coefficients (hologram quantitative structure-activity relationships: r 2 = 0.91, q 2 = 0.78; comparative molecular field analysis: r 2 = 0.98, q 2 = 0.77) were obtained, indicating the potential of these 2D and 3D models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted (calculated) values are in good agreement with the experimental results. The final quantitative structure-activity relationships models, along with the information obtained from 2D contribution maps and 3D contour maps, obtained in this study are useful tools for the design of novel CB1 ligands with improved anti-obesity potency.

Evaluation of anti-inflammatory activity of derivatives from aerial parts of Baccharis uncinella

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Entomopathogenic fungal activity against pupae and adult Haematobia irritans (Diptera: Muscidae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

11-Oxoaerothionin isolated from the marine sponge Aplysina fistularis shows anti-inflammatory activity in LPS-stimulated macrophages

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anti-diabetic activity of Bauhinia forficata decoction in streptozotocin-diabetic rats

The effects of using Bauhinia forficata leaf decoction (150 g leaf/l water; 35.2+/-7.8 ml/100 g body weight mean daily dose) as a drinking-water substitute for about I month on streptozotocin-diabetes (STZ-diabetes) in male Wistar rats were investigated. The physico-metabolic parameters measured were: body weight, food and liquid intake, urinary volume, hepatic glycogen, serum triglycerides and cholesterol, plasma glucose, urinary glucose and urea, and the weight of epididymal and retroperitoneal adipose tissue and soleus and extensor digitorum longus muscles. The STZ-diabetic rats treated with decoction showed a significant reduction in serum and urinary glucose and urinary urea as compared to the STZ-diabetic control, no difference being seen between decoction-treated and -untreated non-diabetic rats. The other physico-metabolic factors showed no changes in treated STZ-diabetic rats. The improvement in carbohydrate metabolism seen in the rats treated with Bauhinia forficata decoction does not appear to be linked to the inhibition of glycogenolysis or the stimulation of glycogenesis nor does it appear to act in a way similar to insulin or the sulfonylureas, although it may act by the inhibition of neoglycogenesis in a manner similar to that of the biguanides. (C) 2002 Elsevier B.V. Ireland Ltd. All rights reserved.

Intestinal anti-inflammatory activity of paepalantine, an isocoumarin isolated from the capitula of Paepalanthus bromelioides, in the trinitrobenzenesulphonic acid model of rat colitis

The preventative intestinal anti-inflammatory activity of paepalantine, an isocoumarin isolated from the capitula of Paepalarithus bromelioides, was tested in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. This was performed in two different experimental settings, i. e. when the colonic mucosa is intact or when the mucosa is in process of recovery after an initial insult. The results obtained revealed that the paepalantine pretreatment, at doses of 5 and 10 mg/kg, significantly attenuated the colonic damage induced by TNBS in both situations, as it was evidenced both histologically and biochemically. This beneficial effect was associated with an improvement in the colonic oxidative status, since paepalantine prevented the glutathione depletion that occurred as a consequence of the colonic inflammation. In addition, the intestinal anti-inflammatory effect exerted by this isocoumarin was associated with an inhibition of colonic nitric oxide activity, which is upregulated as a consequence of the inflammatory process. In conclusion, the preventative effect exerted by paepalantine in the TNBS model of rat colitis is probably related with its antioxidant properties.

Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Gastric anti-ulcer activity of leaf fractions obtained of polar extract from Wilbrandia ebracteata in mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Intestinal Anti-Inflammatory Activity of Baccharis dracunculifolia in the Trinitrobenzenesulphonic Acid Model of Rat Colitis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)