Evaluation and molecular docking study of two flavonoids from Oroxylum indicum (L.) Kurz and their semi-synthetic derivatives as histone deacetylase inhibitors.

Chrysin (5,7-dihydroxyflavone, 6) and galangin 3-methyl ether (5,7-dihydroxy-3-methoxy flavone, 7) were obtained from the leaves of Oroxylum indicum (L.) Kurz in 4% and 6% yields, respectively. Both compounds could act as pan-histone deacetylase (HDAC) inhibitors. Structural modification of these lead compounds provided thirty-eight derivatives which were further tested as HDAC inhibitors. Compounds 6b, 6c, and 6q were the most potent derivatives with the IC50 values of 97.29 ± 0.63 µM, 91.71 ± 0.27 µM, and 96.87 ± 0.45 µM, respectively. Molecular docking study indicated the selectivity of these three compounds toward HDAC8 and the test against HDAC8 showed IC50 values in the same micromolar range. All three compounds were further evaluated for the anti-proliferative activity against HeLa and A549 cell lines. Compound 6q exhibited the best activity against HeLa cell line with the IC50 value of 13.91 ± 0.34 µM. Moreover, 6q was able to increase the acetylation level of histone H3. These promising HDAC inhibitors deserve investigation as chemotherapeutic agents for treating cancer.

Anti-inflammatory effects of Derris scandens extract on narrowband-ultraviolet B exposed HaCaT human keratinocytes.

Narrowband-ultraviolet B (NB-UVB) has been used to treat skin diseases such as psoriasis. Chronic use of NB-UVB might cause skin inflammation and lead to skin cancer. In Thailand, Derris Scandens (Roxb.) Benth. is used as an alternative medicine to nonsteroidal anti-inflammatory drugs (NSAIDs) for low back pain and osteoarthritis. Therefore, this study aimed to evaluate the potential anti-inflammatory effect of Derris scandens extract (DSE) on pre- and post exposed NB-UVB human keratinocytes (HaCaT). The results indicated that DSE could not protect HaCaT from cell morphology changes or DNA fragmentation and could not recover cell proliferation ability from the NB-UVB effects. DSE treatment reduced the expression of genes related to inflammation, collagen degradation, and carcinogenesis, such as IL-1α, IL-1ß, IL-6, iNOS, COX-2, MMP-1, MMP-9, and Bax. These results indicated the potential use of DSE as a topical preparation against NB-UVB-induced inflammation, anti-aging, and prevention of skin cancer from phototherapy.

Neuroprotective and anticancer effects of 7­Methoxyheptaphylline via the TAK1 pathway.

7­Methoxyheptaphylline (7­MH) is a carbazole extracted from Clausena harmandiana, a medicinal plant that is used to treat headaches and stomachaches. The aim of the present study was to examine the neuroprotective effects and anticancer activity of 7­MH. Cell death was assessed using an MTT assay and flow cytometry. The expression of apoptosis­related proteins was determined by western blot analysis. An animal model was used to test anti­metastasis. The interactions between 7­MH and the molecular target were observed using molecular docking. The results revealed that 7­MH provided protection against hydrogen peroxide (H2O2)­induced neuronal cell death. In cancer cells, 7­MH induced SH­SY5Y, 4T1, HT29, HepG2, and LNCaP cell death. 7­MH inhibited metastasis of HT29 cells in vitro and 4T1­Luc cells in vitro and in vivo. 7­MH inhibited proteins, including P­glycogen synthase kinase (GSK)­3, and cleaved caspase­3, but it activated anti­apoptotic proteins in H2O2­induced SH­SY5Y cell death. By contrast, 7­MH activated the cleaving of caspase­3 and GSK­3, but it suppressed anti­apoptotic proteins in SH­SY5Y cells. 7­MH reduced the levels of NF­κB and STAT3 in 4T1 cells; phospho­p65, Erk, and MAPK13 in LNCaP cells; and phospho­Erk and matrix metalloproteinase­9 in HT29 cells. Molecular docking analysis showed that 7­MH targets TAK1 kinase. The present study indicated that 7­MH induced apoptosis of cancer cells and provided protection against H2O2­induced neuron cell death via TAK1 kinase.

A new diarylhexane and two new diarylpropanols from the roots of Knema globularia.

A new diarylhexane, kneglobularone B (1) and two new diarylpropanols, kneglobularols A - B (2 - 3) along with seven known compounds (4 - 10) were isolated and characterized from the roots of Knema globularia. It is the first time to find arylpropyl quinone (4) and isoflavone (8) in Myristicaceae family. In addition, 5 was found for the first time in Knema genus. Their structures were elucidated by UV, IR, MS, 1 D and 2 D NMR techniques. Compound 4 exhibited strong cytotoxicity against the NCI - H187 and MCF - 7 cell lines with IC50 values of 3.08 and 6.68 µg/mL, respectively.

A new flavonoid from the leaves of Atalantia monophylla (L.) DC.

A new flavonoid, atalantraflavone (1) as well as eight known compounds including atalantoflavone (2), racemoflavone (3), 5,4'-dihydroxy-(3″,4″-dihydro-3″,4″-dihydroxy)-2″,2″-dimethylpyrano-(5″,6″:7,8)-flavone (4), lupalbigenin (5), anabellamide (6), citrusinine I (7), p-hydroxybenzaldehyde (8), and frideline (9), were isolated from the leaves of Atalantia monophylla (L.) DC. Focusing on Alzheimer's disease, acetylcholine esterase (AChE) inhibition and antioxidant activity were evaluated using the modified Ellman's method and the ABTS scavenging assay, respectively. It was found that isoflavonoid 5, lupalbigenin, showed 79% inhibition to AChE and was 1.4-fold stronger than the tacrine standard. In addition, acridone 7, citrusinine I, displayed 90.68% antioxidant activity.

New limonophyllines A-C from the stem of Atalantia monophylla and cytotoxicity against cholangiocarcinoma and HepG2 cell lines.

Three new limonoids, limonophyllines A-C (1, 4 and 5), along with two known limonoids (2 and 3) and 11 acridone alkaloids (6-16) were isolated from the stems of Atalantia monophylla. All isolates were evaluated against cholangiocarcinoma, KKU-M156, and HepG2 cancer cell lines. Compounds 12, 14 and 16 displayed cytotoxicity against KKU-M156 cell line with IC50 ranging from 3.39 to 4.1 µg/mL while cytotoxicity against HepG2 cell line with IC50 ranging from 1.43 to 8.4 µg/mL. The structures of all isolated compounds were established by spectroscopic methods including 1D and 2D NMR, IR and mass spectrometry.

Coumarins and alkaloids from the roots of Toddalia asiatica.

The EtOAc and MeOH extracts of the roots of Toddalia asiatica Lam. were investigated for the roots' chemical constituents. Two new compounds including 2'R-acetoxytoddanol (1) and 8S-10-O-demethylbocconoline (3) as well as 15 known compounds were isolated. Compound 10 showed strong cytotoxicity against KB cells with an IC50 value of 2.60 µg/mL, which is nearly equal to the ellipticine standard, but showed no activity against Vero cells. Alkaloid 3 displayed weak cytotoxicity against the KB cell line with an IC50 value of 21.69 µg/mL.

Canangalias C-H, juvenile hormone III analogues from the roots of Cananga latifolia.

Chemical investigation of the roots of Cananga latifolia led to the isolation and purification of thirteen juvenile hormone III analogues. Six new analogues, canangalias C-H (1-6) and a new natural product, (2E,6E,10R)-10-acetoxy-11-hydroxy-3,7,11-trimethyldodeca-2,6-dienoic acid methyl ester (7), were isolated. In addition, six known juvenile hormone III analogues were isolated. Their structures were established by spectroscopic methods including 1D and 2D NMR, IR and mass spectrometry.

Combination of Nimbolide and TNF-α-Increases Human Colon Adenocarcinoma Cell Death through JNK-mediated DR5 Up- regulation.

Tumor necrosis factor (TNF-α), an inflammatory cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis, has previously been used in anti-cancer therapy. However, the therapeutic applications of TNF-α are largely limited due to its general toxicity and anti-apoptotic influence. To overcome this problem, the present study focused on the effect of active constituents isolated from a medicinal plant on TNF-α-induced apoptosis in human colon adenocarcinoma (HT-29) cells. Nimbolide from Azadirachta indica was evaluated for cytotoxicity by methyl tetrazolium 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay and phase contrast microscopy. Effects on apoptotic signaling proteins were investigated using Western blot analysis. Nimbolide showed cytotoxicity against HT-29 cells that was significantly different from the control group (<0.01), a concentration of 10 µM significantly inducing cell death (<0.01). In combination with TNF-α, nimbolide significantly enhanced-induced cell death. In apoptotic pathway, nimbolide activated c-Jun N-terminal kinase (JNK) phosphorylation, BH3 interacting-domain death agonist (Bid) and up-regulated the death receptor 5 (DR5) level. In the combination group, nimbolide markedly sensitized TNF-α-induced JNK, Bid, caspase-3 activation and the up-regulation of DR5. Our findings overall indicate that nimbolide may enhance TNF-α-mediated cellular proliferation inhibition through increasing cell apoptosis of HT-29 cells by up-reglation of DR5 expression via the JNK pathway.

Cytotoxicity of compounds from the fruits of Derris indica against cholangiocarcinoma and HepG2 cell lines.

Two new compounds, derrivanone (1) and derrischalcone (2), were isolated from the crude hexane extract of the fruits of Derris indica. In addition, 14 known compounds were isolated from the fruits of this plant. Chalcones 2-4 showed strong cytotoxicity against cholangiocarcinoma cell line (M156) and human hepatoma HepG2 cells. In addition, flavanones 15 and 16 exhibited potent and high cytotoxic efficacy.

Cytotoxic coumarins from Toddalia asiatica.

Three new coumarins and 13 known compounds were isolated from the stem bark of Toddalia asiatica. Compounds 1, 3, 8, and 9 showed cytotoxicity against the NCI-H187 cell line with IC50 values ranging from 6 to 9 µg/mL. Compounds 4 and 9 exhibited cytotoxicity against the MCF-7 cell line with IC50 values of 3.17 and 9.79 µg/mL, respectively. Compound 9 also displayed cytotoxic activity against KB cells with an IC50 value of 8.63 µg/mL. In addition, compound 14 showed antimalarial activity against Plasmodium falciparum with an IC50 value of 3.66 µg/mL. Compounds 5, 9, and 16 exhibited antituberculosis activity against Mycobacterium tuberculosis with MIC values of 50, 50, and 25 µg/mL, respectively.

Coumarinoids from the fruits of Micromelum falcatum.

Four new compounds, microminutin B (1), microminutin C (2), micromarinate (3), and secomicromelin (4) as well as 17 known compounds were isolated from the fruits of Micromelum falcatum. All compounds were evaluated for antifungal activity against Pythium insidiosum using disc diffusion assay. P. insidiosum is a fungus-like microorganism for which antifungal agents now available are not effective. The results show that four compounds including secomicromelin (4), 7-methoxy-8-(4'-methyl-3'-furanyl)coumarin (10), micromarin B (17), and isomicromelin (19) could inhibit the mycelia growth of P. insidiosum.

Heptaphylline induces apoptosis in human colon adenocarcinoma cells through bid and Akt/NF-κB (p65) pathways.

Heptaphylline derivatives are carbazoles in Clausena harmandiana, a medicinal plant that is utilized for headache, stomach ache, and other treatments of illness. The present study examined the effects of heptaphylline and 7-methoxyheptaphylline on apoptosis of human colon adenocarcinoma cells (HT-29 cell line). Quantification of cell viability was performed using cell proliferation assay (MTT assay) and of protein expression through immunoblotting. The results showed that only heptaphylline, but not 7-methoxyheptaphylline, significantly significantly activated cleaved of caspase-3 and poly (ADP-ribose) polymerase (PARP-1) which resulted in HT-29 cell death. We found that heptaphylline activated BH3 interacting-domain death agonist (Bid) and Bak, proapoptotic proteins. In contrast, it suppressed X-linked inhibitor-of-apoptosis protein (XIAP), Bcl-xL and survivin, inhibitors of apoptosis. In addition, heptaphylline inhibited activation of NF-κB/p65 (rel), a regulator of apoptotic regulating proteins by suppressing the activation of Akt and IKKα, upstream regulators of p65. The findings suggested that heptaphylline induces apoptosis in human colon adenocarcinoma cells .

New lignan esters from Alyxia schlechteri and antifungal activity against Pythium insidiosum.

Three new lignan esters, alyterinates A-C (1-3), as well as 10 known compounds were isolated from the roots of Alyxia schlechteri. Antifungal activity against Pythium insidiosum of all lignan derivatives was evaluated using disk diffusion assay. P. insidiosum is not a true fungus since its cell walls do not contain ergosterol as usual fungi, so the antifungals available now are not effective. From activity testing, it was found that compounds 3, 4 and 5 could inhibit the mycelia growth of P. insidiosum.

Clauraila E from the roots of Clausena harmandiana and antifungal activity against Pythium insidiosum.

A new carbazole alkaloid named clauraila E (1) together with 8 known compounds were isolated from the methanol extract of the roots of Clausena harmandiana. All compounds were evaluated for antifungal activity against Pythium insidiosum using disc diffusion assay. Pythium insidiosum is a fungus-like microorganism, for which antifungals available now are not effective. It was found that compounds 3, 6, 7 and 9 could inhibit the mycelia growth of P. insidiosum. The results show convincingly that they may be lead to compounds for the development of probiotic or novel antifungal drugs.

Cytotoxicity of chemical constituents from the stems of Dalbergia parviflora.

Three new compounds, dalberpene, dalparvinene B and dalparvone B, as well as 12 known compounds were isolated from the heartwood of Dalbergia parviflora. Isoflavanone 13 showed strong cytotoxicity against KB, MCF-7 and NCI-H187 cell lines with IC50 values ranging from 3.5 to 5.4µg/mL and it was inactive against normal cells.

Carbazoles and coumarins from Clausena harmandiana stimulate glucose uptake in L6 myotubes.

Two carbazoles (compounds 1 and 2) and one coumarin (compound 8) from Clausena harmandiana exhibited significant glucose uptake activity in L6 myotubes in a time and dose dependent manner. In addition, compounds 2 and 8 were inhibited by p38 mitogen-activated protein kinases and phosphatidylinositol 3-kinases, respectively.

Biological activity of chemical constituents from Clausena harmandiana.

The activity guided fractionation of the Clausena harmandiana root extracts led to the isolation of a coumarin, a ferulate, and eight carbazoles. This is the first report of the isolation of compounds 2-4 and 6-10 from this species, and this is the first time 10 was isolated from this genus. Compound 4 showed strong cytotoxicity against NCI-H187 cells with an IC(50) value of 1.63 microg/mL. Compound 5 demonstrated strong cytotoxicity against MCF-7 and KB cell lines with IC50 values of 2.21 and 1.74 microg/mL, respectively. Compounds 3 and 4 exhibited moderate cytotoxicity against the MCF-7 cell line, and 8 showed moderate cytotoxicity against NCIH187 and KB cell lines. Compounds 3 and 5 showed antiplasmodial activity with IC(50) values of 3.27 and 2.94 microg/mL, respectively.

Bioactive constituents from the stems of Dalbergia parviflora.

From the stems of Dalbergia parviflora, three known flavonoids, six known isoflavonoids, a new isoflavone, dalparvone (2) and a new cinnamyl derivative, dalparvinene (6) were isolated and characterized. Isoflavan 3 exhibited strong cytotoxicity against KB and NCI-H187 cell lines with IC(50) values of 0.53 and 2.04 microg/ml, respectively. Compound 6 demonstrated strong cytotoxicity against NCI-H187 with an IC(50) value of 1.46 microg/ml. Compounds 4 and 6 possessed moderate cytotoxicity against KB cells with IC(50) values of 6.78 and 9.89 microg/ml, respectively. In addition, 2 exhibited moderate antiplasmodial activity with an IC(50) value of 8.19 microg/ml.

Effects of Kaempferia parviflora extracts and their flavone constituents on P-glycoprotein function.

The purpose of this study was to examine the effects of extracts and flavone derivatives from the rhizome of Kaempferia parviflora on P-glycoprotein (P-gp)-mediated transport in LLC-GA5-COL150, a transfectant cell line of a porcine kidney epithelial cell line LLC-PK1 with human MDR1 cDNA. Ethanol extract obtained from Kaempferia parviflora rhizome significantly increased the accumulation of rhodamine 123 and daunorubicin, P-gp substrates, in LLC-GA5-COL150 cells, but not in LLC-PK1 cells. The aqueous extract also increased the accumulation in LLC-GA5-COL150 cells with lower potency than the ethanol extract. The effects of flavone derivatives isolated from the rhizome of Kaempferia parviflora on P-gp function were examined. Among six flavones tested, 3,5,7,3',4'-pentamethoxyflavone most potently increased the accumulation of rhodamine 123 and daunorubicin in LLC-GA5-COL150 cells in a concentration-dependent manner. In addition, 5,7-dimethoxyflavone to lesser degree increased rhodamine 123 accumulation in LLC-GA5-COL150 cells. In contrast, the other four flavone derivatives had no significant effect on the accumulation of rhodamine 123 in LLC-GA5-COL150 cells in a concentration range tested. These results indicate that extracts and flavone derivatives from the rhizome of Kaempferia parviflora can inhibit P-gp function, which may be useful for overcoming P-gp-mediated multidrug resistance and improving the oral bioavailability of anticancer agents.